Systems and methods for assessing pulmonary gas transfer using hyperpolarized 129XE MRI

ABSTRACT

Methods and systems for assessing pulmonary gas exchange and/or alveolar-capillary barrier status include obtaining at least one MRI image and/or image data of  129 Xe dissolved in the red blood cells (RBC) in the gas exchange regions of the lungs of a patient. The image is sufficiently sensitive to allow a clinician or image recognition program to assess at least one of pulmonary gas exchange, barrier thickness or barrier function based on the  129 Xe MRI RBC image.

RELATED APPLICATION

This application claims the benefit of priority of U.S. ProvisionalApplication Ser. No. 60/827,983, filed Oct. 3, 2006, the contents ofwhich are hereby incorporated by reference herein.

GOVERNMENT GRANTS

The invention was carried out using government grants including a grantfrom the NCRR/NCI National Biomedical Technology Resource Center (P41RR005959/R24 CA 092656) and a grant from the National Institutes ofHealth, NIH/NHLBI (R01 HL055348). The United States government hascertain rights to this invention.

RESERVATION OF COPYRIGHT

A portion of the disclosure of this patent document contains material towhich a claim of copyright protection is made. The copyright owner hasno objection to the facsimile or reproduction by anyone of the patentdocument or the patent disclosure, as it appears in the Patent andTrademark Office patent file or records, but reserves all other rightswhatsoever.

FIELD OF THE INVENTION

The invention relates to NMR spectroscopy and MRI (Magnetic ResonanceImaging).

BACKGROUND OF THE INVENTION

The exchange of gases in the lung requires ventilation, perfusion andthe diffusion of gases across the blood-gas barrier of the alveoli.While pulmonary ventilation (1, 2) and perfusion (3, 4) can be examinedby a variety of imaging techniques, currently no methods exist to imagealveolar-capillary gas transfer. Unfortunately, certain pulmonarypathologies such as, for example, inflammation, fibrosis, and edema mayinitially have a predominant effect on the gas exchange process, but notventilation or perfusion. The degree to which a “diffusion block” (5) ispresent or absent in the blood-gas barrier has been difficult todetermine in studies to date (6). In healthy alveoli, the harmonic meanthickness [as defined by Weibel (7) of the blood-gas barrier is about0.77 μm and oxygen traverses this space in less than a millisecond,saturating the red blood cells (RBCs) in tens of milliseconds. However,in regions where the barrier is thickened, oxygen may be undesirablyprevented from diffusing across the barrier fast enough to saturate theRBCs before they exit the gas exchange region [estimated at about 750 msin humans (5), 300 ms in rats (8).

SUMMARY OF EMBODIMENTS OF THE INVENTION

Embodiments of the present invention provide systems and methods tonon-invasively obtain spectra or image data associated withalveolar-capillary gas transfer using hyperpolarized ¹²⁹Xe. The imagescan be direct images that visually reflect the barrier's ability (orinability) to transfer gas to red blood cells.

Embodiments of the invention provide images that can be useful todiagnose lung diseases or injury, study or evaluate interstitial lungdiseases or injury and/or the progression or abatement thereof, and/orevaluate the efficacy of directed therapies the side effects or theinadvertent negative effects of therapies or drug treatments onalveolar-capillary gas transfer.

Some embodiments are directed to methods for assessing pulmonary gasexchange and/or alveolar-capillary barrier status. The methods include:(a) transmitting an RF MRI excitation pulse sequence configured toexcite dissolved phase hyperpolarized ¹²⁹Xe in a gas exchange region ofa lung of a subject; and (b) obtaining image data of a dissolved phase¹²⁹Xe MRI red blood cell (RBC) compartment in the gas exchange region ofthe lung of the subject based on the transmission.

The obtained at least one ¹²⁹Xe MRI RBC image may be obtained using a RFpulse repetition time of between about 10-200 ms, typically betweenabout 10-60 ms, and more typically between about 10-50 ms and optionallya large angle excitation pulse (such as about 90 degrees).

The obtained image may be used to assess at least one of pulmonary gasexchange, barrier thickness or barrier function based on the ¹²⁹Xe MRIRBC image.

The methods may optionally include also generating the RBC compartmentimage and obtaining at least one dissolved phase ¹²⁹Xe MRI barrier imagesignal data of the gas exchange region of the lung and generating abarrier image. The assessing step may include displaying the obtainedRBC and barrier images concurrently. The assessing step may includeelectronically or visually comparing the obtained ¹²⁹Xe RBC and barrierimages to detect dissolved phase ¹²⁹Xe MRI signal attenuation in the¹²⁹Xe RBC image. In particular embodiments, the step of obtaining atleast one ¹²⁹Xe MRI RBC image signal data and the step of obtaining¹²⁹Xe MRI barrier image signal data may each include obtaining aplurality of respective images with different RF pulse repetition times(TR) of between about 0-60 ms to define signal replenishment on a pixelby pixel basis.

The ¹²⁹Xe dissolved phase image signal data may be obtained using aradial imaging sequence and/or a spin-echo imaging sequence.

The obtained ¹²⁹Xe MRI RBC (and barrier) image may be generated based ona one-point Dixon mathematical evaluation of MRI dissolved phase ¹²⁹Xesignal data comprising both RBC signal data and barrier signal data tothereby differentiate the signal data.

The method may further include obtaining gas-phase ¹²⁹Xe MRI imagesignal data of the patient. Also, the method may optionally includeelectronically generating a field map of spatially varying field shiftscorresponding to magnetic field inhomogeneity associated with an MRIscanner used to generate the obtained gas-phase ¹²⁹Xe image signal data;and electronically correcting signal data associated with dissolvedphase ¹²⁹Xe MRI RBC and barrier images using the field-map of fieldshifts.

Still other embodiments are directed to methods of assessing pulmonarygas exchange and/or thickening or function of the blood-gas barrier. Themethods include: (a) obtaining dissolved phase hyperpolarized ¹²⁹Xe NMRspectra having peaks (at about 211 ppm, which for a 2 T system is 5kHz)) associated with red blood cells (RBC); (b) obtaining dissolvedphase hyperpolarized ¹²⁹Xe MRI spectra having peaks (at about 197 ppm,(which for a 2 T system the shift is at about 4.66 k kHz) associatedwith a blood-gas barrier; and (c) evaluating a lung based the dissolvedphase ¹²⁹Xe RBC and barrier spectra peaks.

The spectroscopy method may also include obtaining gas-phase ¹²⁹Xespectra at 0 ppm and comparing the magnitude, height and/or size ofpeaks in the gas-phase spectra with the dissolved phase spectra toassess pulmonary gas exchange, interstitial lung disease or injury orefficacy of a treatment therefor. Interstitial lung injury or diseasemay be associated with reduced RBC peak size or height relative tobarrier peak size or height. The obtained dissolved phase NMR spectracan be generated using short excitation pulse repetition times (TR)between about 10-200 ms.

Yet other embodiments are directed to methods of generating athree-dimensional ¹²⁹Xe MRI image of a lung. The methods includegenerating a three-dimensional image of a blood-gas barrier of a lungusing dissolved phase ¹²⁹Xe MRI image signal replenishment data todefine barrier thickness and/or impaired barrier function. The methodmay further include employing radial projection encoding withphase-sensitive image reconstruction to generate the three-dimensionalimage. A ratio image may also be generated using ratios of barrier andRBC image signal data. The ratio image may be used to illustrate and/orvisualize signal attenuation.

In some embodiments, the generating step includes acquiring a pluralityof dissolved phase ¹²⁹Xe images at multiple repetition times todetermine barrier thickness and ¹²⁹Xe diffusion. The method may includegenerating sufficient dissolved phase RBC and barrier image data tocurve fit signal replenishment on a pixel-by-pixel basis.

In particular embodiments, the generating the image step includeselectronically evaluating signal data using a one-point Dixon evaluationof MRI dissolved phase ¹²⁹Xe dissolved phase signal data comprising bothRBC signal data and barrier signal data.

Still other embodiments are directed to MRI scanner systems. The MRIscanner systems include: (a) an MRI scanner; and (b) an MRI receiverwith a plurality of channels in communication with the MRI scanner,including a first channel configured to receive ¹²⁹Xe RBC image data anda second channel configured to receive ¹²⁹Xe barrier image data. The MRIscanner is configured to programmatically set the MRI scanner frequencyand phase to a ¹²⁹Xe dissolved phase imaging mode whereby the scannerfrequency and phase is electronically adjusted for xenonalveolar-capillary transfer imaging.

In some embodiments, the first channel receiver phase can be set suchthat a RBC resonance (such as 211 ppm) corresponds to a real channel andthe second channel receiver phase can be set such that a barrierresonance (such as 197 ppm) lags about 90 degrees behind in a negativeimaginary channel. Alternatively, the RBC channel can be at +90 degrees(imaginary) and the barrier channel can be at 0 degrees (real).

The MRI scanner may include a scanning sequence that automaticallyswitches the MRI scanner frequency from ¹²⁹Xe gas to dissolved phase,then back to ¹²⁹Xe gas phase to thereby acquire portions of gas anddissolved image data sets in an interleaved manner. The MRI scanner maybe configured to provide a first ¹²⁹Xe MRI RBC image of the lung and asecond corresponding ¹²⁹Xe MRI barrier image of the lung andelectronically display the two images substantially concurrently side byside.

Still other embodiments are directed to computer program products forgenerating ¹²⁹Xe MRI images of capillary beds in lungs. The productsinclude computer readable storage medium having computer readableprogram code embodied therein. The computer readable program codeincludes computer readable program code configured to obtain a dissolvedphase MRI signal of ¹²⁹Xe associated with red blood cells in a lung,wherein signal attenuation in the image is associated with reducedalveolar capillary transfer capacity. The program product may also oralternatively include: (a) computer readable program code configured toobtain a dissolved phase MRI signal of ¹²⁹Xe associated with aalveolar-capillary barrier in the lung; and (b) computer readableprogram code configured to obtain an MRI signal of ¹²⁹Xe in an air spaceof the lung.

Although described herein with respect to method aspects of the presentinvention, it will be understood that the present invention may also beembodied as systems and computer program products.

Other systems, methods, and/or computer program products according toembodiments of the invention will be or become apparent to one withskill in the art upon review of the following drawings and detaileddescription. It is intended that all such additional systems, methods,and/or computer program products be included within this description, bewithin the scope of the present invention, and be protected by theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features of the present invention will be more readily understoodfrom the following detailed description of exemplary embodiments thereofwhen read in conjunction with the accompanying drawings, in which:

FIG. 1A is a one-dimensional model of gas transfer and signalreplenishment in the barrier tissue and RBCs using a simplifieddepiction of the alveolar capillary unit and corresponding ¹²⁹Xe NMRresonance frequencies in air space, barrier, and RBCs.

FIG. 1B is a three-dimensional graph of position (μm), time (ms) and¹²⁹Xe magnetization of dissolved ¹²⁹Xe replenishment.

FIG. 1C is a graph of barrier signal (197 ppm) replenishment versus time(ms) for barrier thicknesses ΔL_(db) ranging from 1 μm to 7.5 μm.

FIG. 1D is a graph of RBC signal (211 ppm) replenishment versus time(ms) for the same range of barrier thickness as in FIG. 1C and constantL_(c)=4 μm.

FIGS. 2A-2C are digital images of ¹²⁹Xe in an airspace, barrier and RBCof a “sham” animal.

FIGS. 2D-2F are corresponding digital ¹²⁹Xe images of an injured animalpresenting with left lung fibrosis 11 days post-instillation ofbleomycin.

FIGS. 3A and 3B are Hematoxylin Eosin (H&E) stained histology. FIG. 3Ais a specimen of a control left lung from a right-lung instilled animal.FIG. 3B is a specimen of a damage left lung from a bleomycin-instilledanimal.

FIG. 4 is a graph of a ratio of normalized ¹²⁹Xe pixel count in barrierand RBC images versus pixel count in the airspace images of each lung.The graph also includes a regression line that is fit to all of thebarrier pixel counts in injured and uninjured lungs.

FIGS. 5A and 5C are dynamic spectroscopy graphs of delay times (ms)versus chemical shift (ppm). FIG. 5A is a graph of dynamic spectra of acontrol animal and FIG. 5B is a graph of dynamic spectra of an injuredanimal (rat).

FIGS. 5B and 5D are graphs of signal replenishment, signal integral(arbitrary) versus pulse repetition time (TR) for the barrier and bloodcompartments. FIG. 5B corresponds to the control animal and FIG. 5Dcorresponds to the injured animal (rat).

FIG. 6 is a flow chart of exemplary operations that can be used to carryout methods according to some embodiments of the present invention.

FIG. 7 is a flow chart of steps that can be used to carry outembodiments of the present invention.

FIG. 8 is a schematic illustration of an MRI scanner according toembodiments of the present invention.

FIG. 9A is a block diagram of data processing systems that may be usedto generate ¹²⁹Xe images in accordance with some embodiments of thepresent invention.

FIG. 9B is a block diagram of data processing systems that may be usedto generate ¹²⁹Xe gas transfer ratios of pixels associated with RBC andbarrier spectra accordance with some embodiments of the presentinvention.

FIG. 10A is a conventional 3-D projection k-space trajectory.

FIG. 10B is an efficient 3-D trajectory using 30% fewer radialprojections than the conventional model, covering k-space with 9329frames for a 64×64×16 image, according to embodiments of the presentinvention.

FIGS. 11A-11B are phase-sensitive ¹²⁹Xe ventilation (airspace) digitalimages of a lung. FIG. 11A is a real channel image. FIG. 11B is aimaginary channel image.

FIG. 11C is a phase map generated from the airspace image of data fromFIGS. 11A and 11B. The phase variation is due to B_(o) inhomogeneity.

FIGS. 12A and 12B are graphs of phases of 211 ppm (RBC) and 197 ppm(barrier) resonances. FIG. 12A illustrates the “assumed” phases based onthe respective channel allocation (imaginary and real) of the receiveraccording to embodiments of the present invention. FIG. 12B illustrates“correctable” local misalignment of signal phases due to phase shiftscaused by B_(o) variation according to embodiments of the presentinvention.

FIG. 13A is a screen printout of barrier images of a healthy rat withdifferent pulse repetition times (TR, 10, 15, 25 and 50) according toembodiments of the present invention.

FIG. 13B is a screen printout of RBC images of a healthy rat withdifferent pulse repetition times (TR, 10, 15, 25 and 50) correspondingto the barrier images in FIG. 13A according to embodiments of thepresent invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

While the invention may be made in modified and alternative forms,specific embodiments thereof are shown by way of example in the drawingsand will be described in detail. It should be understood, however, thatthere is no intent to limit the invention to the particular formsdisclosed, but on the contrary, the invention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the invention. Like reference numbers signify like elementsthroughout the description of the figures.

In the figures, the thickness of certain lines, layers, components,elements or features may be exaggerated for clarity. Broken linesillustrate optional features or operations unless specified otherwise.The sequence of operations (or steps) is not limited to the orderpresented in the claims or figures unless specifically indicatedotherwise.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof. As used herein, the term “and/or”includes any and all combinations of one or more of the associatedlisted items. As used herein, phrases such as “between X and Y” and“between about X and Y” should be interpreted to include X and Y. Asused herein, phrases such as “between about X and Y” mean “between aboutX and about Y.” As used herein, phrases such as “from about X to Y” mean“from about X to about Y.”

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

It will be understood that, although the terms first, second, etc. maybe used herein to describe various elements, components, regions, layersand/or sections, these elements, components, regions, layers and/orsections should not be limited by these terms. These terms are only usedto distinguish one element, component, region, layer or section fromanother region, layer or section. Thus, a first element, component,region, layer or section discussed below could be termed a secondelement, component, region, layer or section without departing from theteachings of the present invention.

The term “MRI scanner” refers to a magnetic resonance imaging and/or NMRspectroscopy system. As is well known, the MRI scanners include a lowfield strength magnet (typically between about 0.1 T to about 0.5 T), amedium field strength magnet, or a high-field strength super-conductingmagnet, an RF pulse excitation system, and a gradient field system. MRIscanners are well known to those of skill in the art. Examples ofcommercially available clinical MRI scanners include, for example, thoseprovided by General Electric Medical Systems, Siemens, Philips, Varian,Bruker, Marconi, Hitachi and Toshiba. The MRI systems can be anysuitable magnetic field strength, such as, for example, about 1.5 T, andmay be higher field systems of between about 2.0 T-10.0 T.

The term “high-field strength” refers to magnetic field strengths above1.0 T, typically above 1.5 T, such as 2.0 T. However, the presentinvention is not limited to these field strengths and may suitable foruse with higher field strength magnets, such as, for example, 3 T-10 T,or even greater.

The term “hyperpolarized” ¹²⁹Xe refers to ¹²⁹Xe that has increasedpolarization over natural or equilibrium levels. As is known by those ofskill in the art, hyperpolarization can be induced by spin-exchange withan optically pumped alkali-metal vapor or alternatively by metastabilityexchange. See Albert et al., U.S. Pat. No. 5,545,396; and Cates et al,U.S. Pat. No. 5,642,625 and U.S. Pat. No. 5,809,801. These referencesare hereby incorporated by reference as if recited in full herein. Onepolarizer that is suitable for generating the hyperpolarized ¹²⁹Xe isthe IGI-9600® polarizer (Inert Gas Imaging) made by Magnetic ImagingTechnologies, Durham, N.C. Thus, as used herein, the terms“hyperpolarize”, “polarize”, and the like mean to artificially enhancethe polarization of certain noble gas nuclei over the natural orequilibrium levels.

The term “automatically” means that the operation can be substantially,and typically entirely, carried out without human or manual input, andis typically programmatically directed or carried out. The term“electronically” includes both wireless and wired connections betweencomponents. The term “programmatically” means under the direction of acomputer program that communicates with electronic circuits and otherhardware and/or software.

The term “3-D image” refers to visualization in 2-D what appear to be3-D images using volume data that can represent features with differentvisual characteristics such as with differing intensity, opacity, color,texture and the like. For example, the 3-D image of the lung can begenerated to illustrate differences in barrier thickness using color oropacity differences over the image volume. Thus, the term “3-D” inrelation to images does not require actual 3-D viewability (such as with3-D glasses), just a 3-D appearance, typically on a display. The 3-Dimages comprise multiple 2D slices. The 3-D images can be volumerenderings well known to those of skill in the art and/or a series of2-D slices, which can be visually paged through.

Embodiments of the invention may be particularly suitable for use withhuman patients but may also be used with any animal or other mammaliansubject.

The present invention may be embodied as systems, methods, and/orcomputer program products. Accordingly, the present invention may beembodied in hardware and/or in software (including firmware, residentsoftware, micro-code, etc.). Furthermore, the present invention may takethe form of a computer program product on a computer-usable orcomputer-readable storage medium having computer-usable orcomputer-readable program code embodied in the medium for use by or inconnection with an instruction execution system. In the context of thisdocument, a computer-usable or computer-readable medium may be anymedium that can contain, store, communicate, propagate, or transport theprogram for use by or in connection with the instruction executionsystem, apparatus, or device.

The computer-usable or computer-readable medium may be, for example, anelectronic, magnetic, optical, electromagnetic, infrared, orsemiconductor system, apparatus, device, or propagation medium. Morespecific examples (a non-exhaustive list) of the computer-readablemedium would include the following: an electrical connection having oneor more wires, a portable computer diskette, a random access memory(RAM), a read-only memory (ROM), an erasable programmable read-onlymemory (EPROM or Flash memory), an optical fiber, and a portable compactdisc read-only memory (CD-ROM). Note that the computer-usable orcomputer-readable medium could even be paper or another suitable medium,upon which the program is printed, as the program can be electronicallycaptured, via, for instance, optical scanning of the paper or othermedium, then compiled, interpreted, or otherwise processed in a suitablemanner, if necessary, and then stored in a computer memory. Furthermore,the user's computer, the remote computer, or both, may be integratedinto or communicate with other systems, such as MRI scanner systems.

Generally stated, embodiments of the present invention are directed tonovel methods of obtaining MRI or NMR signal data of dissolved phase(hyperpolarized) ¹²⁹Xe in compartments of the lung associated with gasexchange, including the blood-gas barrier (also known as thealveolar-capillary barrier or “barrier”) and/or RBCs.

The present invention can be used to evaluate, qualitatively orquantitatively, a number of lung disorders, conditions, injuries,disease states, disease and the progression or regression thereof. Forexample, in some embodiments, ¹²⁹Xe MRI imaging can show the effects ofa thickened blood gas barrier at a single repetition time (TR), whicheffectively sets a threshold for barrier thickness. For example at TR=50ms, a barrier greater than 5 μm will appear dark on the RBC image, whilea barrier less than 5 μm will appear bright. As will be discussedfurther below, multiple different repetition times (TR) may also beused, such as, for example, TR between 10-60 ms.

Embodiments of the invention provide clinical evaluation tools and/orresearch tools that are sensitive to blood gas barrier changes. Forexample, some embodiments of the invention can be used to differentiateuncertain aetiology of breathlessness or shortness of breath (or otherbreathing impairments) such as to identify respiratory origin, todetermine the adequacy of the alveolar-capillary unit, system orfunction, and to monitor therapeutic efficacy of treatments on thoseconditions. In other embodiments, the biophysical or biofunctionalreaction to drugs can be assessed during drug discovery programs and/orclinical trials (animal and/or human) and the like to help establish theclinical efficacy and/or negative side effect(s) of the proposed drug.

Still other examples of conditions that may be detected or evaluatedusing some embodiments of the invention include: (a) detection ofalveolitis (inflammation in the alveoli, which inflammation may be aside effect of new drug therapies (the methods may be used to screen newcompounds to see whether they cause inflammation)); (b) detection ofedema (fluid leakage into the alveoli); (c) detection of pneumonia(infection in the alveoli); (d) detection of fibrosis (increasedcollagen deposition in the blood-gas barrier (fibrosis can be acomplication of radiation therapy of the lung)); and (e) evaluation ofdrug efficacy for decreased or increased blood gas barrier thickness.

While embodiments of the invention may be particularly suitable forevaluating interstitial lung diseases, the techniques can also beapplied to other areas. For example, some methods can be configured todetect emphysema—a decrease in gas exchange surface area (less tissue).In this analysis, a reduction in barrier signal as well as RBC signal(since both tissue and RBC capillary are destroyed) would be expectedfor this disease state. Also, some methods may be able to detect apulmonary embolism. That is, depending on the location of the blockage,for example, a blockage upstream from capillaries may impact whether theremaining blood stays in the capillaries or is drained. If the blooddrains, then a major reduction in RBC signal would result. If it staysin the capillaries, but just is not flowing, then the xenonaveloar-capillary transfer methods would likely be unaffected. Also, themethods may distinguish the degree of emphysema vs. fibrosis.

In certain embodiments, operations of the invention can be carried outusing hyperpolarized ¹²⁹Xe to evaluate respiratory and/or pulmonarydisorders. For example, ¹²⁹Xe image data and/or NMR spectroscopicsignals of ¹²⁹Xe can be used to obtain data regarding pulmonaryphysiology and/or function in order to assess, diagnose, or monitor oneor more of: a potential bioreaction to a transplant, such as transplantrejection (of transplanted organs in the body, whether lung, heart,liver, kidney, or some other organ of interest), environmental lungdisorders, pneumonitis/fibrosis, pulmonary hypertension, pulmonaryinflammation such as interstitial and/or alveolar inflammation,interstitial lung diseases or disorders, pulmonary and/or alveolar edemawith or without alveolar hemorrhage, pulmonary emboli, drug-inducedpulmonary disorders, diffuse lung disorders, chronic obstructivepulmonary disease, pneumoconiosis, tuberculosis, pleural thickening,cystic fibrosis, pneumothorax, non-cardiogenic pulmonary edema,angioneurotic edema, angioedema, type I alveolar epithelial cellnecrosis, hyaline membrane formation, diffuse alveolar damage such asproliferation of atypical type II pneumocytes, interstitial fibrosis,interstitial and/or alveolar infiltrates, alveolar septal edema, chronicpneumonitis/fibrosis, bronchospasm, bronchialitis obliterans, alveolarhemorrhage, aspiration pneumonia, hypercapnic respiratory failure,alveolitis/fibrosis syndrome, systemic lupus erythematosus, chroniceosinophilic pneumonia, acute respiratory distress syndrome, and thelike.

The lung can be a target of drug toxicity. It is known, for example,that many medications, including chemotherapeutic drugs,anti-inflammatory drugs, anti-microbial agents, cardiac drugs andanticonvulsants can cause lung injury, including lung toxicity, that canbe progressive and result in respiratory failure. See Diffuse LungDisorders: A Comprehensive Clinical-Radiological Overview, Ch. 19,Drug-Induced Pulmonary Disorders, (Springer-Verlag London Ltd, 1999),the contents of which are hereby incorporated by reference as if recitedin full herein. Examples of drug-induced lung disorders that may be ableto be evaluated according to embodiments of the present inventioninclude, but are not limited to: pneumonitis/fibrosis, interstitial lungdisease, interstitial or pulmonary honeycombing and/or fibrosis,hypersensitivity lung disease, non-cardiogenic pulmonary edema, systemiclupus erythematosus, bronchiolitis obliterans, pulmonary-renal syndrome,bronchospasm, alveolar hypoventilation, cancer chemotherapy-induced lungdisease, pulmonary nodules, acute chest pain syndrome, pulmonaryinfiltrates, pleural effusion and interstitial infiltrates, angioedema,cellular atypia, diffuse reticular or reticulonodular infiltrates,bilateral interstitial infiltrates, reduced diffusing capacity,parenchymal damage with alveolar epithelial hyperplasia and fibrosisand/or atypia, early onset pulmonary fibrosis, late-onset pulmonaryfibrosis, and subacute interstitial lung disease.

Some of the above-conditions have been known to occur with specificdrugs, such as mitomycin and bleomycin, and, in certain embodiments ofthe invention, MRI-data and/or NMR-derived data of hyperpolarized ¹²⁹Xecan be used while the patient is being treated with the potentiallyproblematic drug to allow earlier intervention or alternate treatmentsshould the lung exhibit a drug-induced disorder.

In some situations, patients can experience the onset of lung injury atthe early onset of treatment with a therapeutic agent or in a certainenvironment. However, presentation of the injury can be delayed. Incertain situations, the symptoms can present acutely with rapiddeterioration. In either case, early identification of the problem canallow earlier intervention.

Effective pulmonary gas exchange relies on the free diffusion of gasesacross the thin tissue barrier separating air space from the capillaryRBCs. Pulmonary pathologies, such as inflammation, fibrosis, and edema,which cause an increased blood-gas barrier thickness, impair theefficiency of this exchange. However, definitive assessment of suchgas-exchange abnormalities is challenging because no known methodsdirectly image the gas transfer process. Embodiments of the instantinvention can exploit the solubility and chemical shift of ¹²⁹Xe, themagnetic resonance (MR) signal of which has been enhanced by 10⁵ viahyperpolarization, to differentially image its transfer from the airspaces into the tissue barrier spaces and RBCs in the gas exchangeregions of the lung. The novel MR imaging (or NMR spectroscopy) methodsfor evaluating ¹²⁹Xe alveolar-capillary transfer are sensitive tochanges in blood-gas barrier thickness of approximately 5 μm. Theimaging methods have allowed successful separation of tissue barrier andRBC images of a rat model of pulmonary fibrosis where ¹²⁹Xereplenishment of the red blood cells is severely impaired in regions oflung injury.

While not wishing to be bound to any particular theory, it is presentlybelieved that three properties of ¹²⁹Xe make it well suited for magneticresonance imaging (MRI) of the pulmonary gas exchange process and/or NMRspectroscopy of barrier and RBC compartments that can be used toevaluate the gas exchange process or health status of the lung(s).First, xenon is soluble in the pulmonary tissue barrier and RBCcompartments. Second, ¹²⁹Xe resonates at three distinct frequencies inthe air space, tissue barrier, and RBC compartments. Third, the ¹²⁹Xemagnetic resonance signals can be enhanced by a factor of ˜10⁵ making itpossible to image this gas with a resolution approaching proton-MRI.

When ¹²⁹Xe is inhaled into the lung and enters into the alveolarair-spaces, a small fraction is absorbed into the moist epithelialsurface. The atoms diffuse across the tissue barrier and theirconcentration in the RBCs in the capillary beds equilibrates with thatin the air-space. The atoms continue to exchange among all threecompartments before those in the RBCs and plasma are carried away in thepulmonary circulation. When ¹²⁹Xe dissolves, its NMR frequency shiftsdramatically from the free gas frequency. ¹²⁹Xe in the alveolarepithelium, interstitium, capillary endothelium, and plasma resonate ata frequency that is shifted 197 parts per million (ppm) (4.64 kHz in a 2Tesla field) from the gas reference frequency at 0 ppm (9). Since thesetissues lie between the air space and RBCs, this group of 197 ppmshifted signals can be referred to as the “barrier” resonance. Once¹²⁹Xe leaves the barrier and reaches the red blood cells its resonantfrequency shifts yet again to 211 ppm from the gas frequency (10) andthis can be referred to as the “RBC” resonance. Collectively the 197 ppmand 211 ppm signals are referred to as the “dissolved phase,” consistentwith prior literature.

211 ppm B0 gas (MHz) 197 ppm (Hz) (Hz) 1.5 T   17.73 3493 3741 3 T 35.466986 7482 7 T 82.74 16300 17458

In the past, it is believed that Ruppert et al. first used dynamicspectroscopy to measure the replenishment rate of ¹²⁹Xe signal in thebarrier and RBC compartments of the lung after magnetization therein wasdestroyed by a frequency-selective radio frequency (rf) pulse (11).Unlike conventional proton MRI, once the hyperpolarized noble gas atomsare depolarized by the rf pulse, their thermal re-polarization by thestatic magnetic field is negligible and thus, as probes, become silent.The 197 ppm and 211 ppm signals are only replenished as fresh gas phase¹²⁹Xe magnetization diffuses back into the dissolved phase compartmentson a time scale of ˜30-40 ms in a healthy lung. Mansson and co-workersused this spectroscopic technique to show that the time constants forthe barrier and RBC signal replenishment were significantly increased inrat lungs that had been exposed to the inflammatory agent,lipo-polysaccharide (8). Recently, Abdeen and co-workers have usedsimilar methods to show reduce gas transfer in cases of lunginflammation induced by instillation of Stachybotrys chartarum (12).

The present invention recognizes that one aspect of ¹²⁹Xe gas exchangethat is sensitive to blood-gas barrier health status, however, is thetime it takes ¹²⁹Xe to reach the red blood cells. To exhibit the 211 ppmblood resonance, ¹²⁹Xe must first traverse the 197 ppm barrierseparating RBCs from the air space, thus delaying the RBC signalappearance. The time-constant for ¹²⁹Xe diffusion across this barriercan be estimated as τ≈ΔL_(db) ²/2D, where ΔL_(dh) is the barrierthickness and D is the Xe diffusion coefficient. In a healthy subject(rat/human) with a blood-gas barrier of thickness ˜1 μm, and D≈0.33×10⁻⁵cm²s⁻¹ (13), ¹²⁹Xe transit takes only 1.5 ms. Such a delay is shortcompared to MR imaging repetition rates (TR) of 5-10 ms and therefore isdifficult to detect. However, because diffusing time scales as thesquare of the barrier size, a thickness increase to 5 μm would delay theappearance of the 211 ppm resonance by about 40 ms, a timescale moreeasily probed. It is believed that such a striking delay of the RBCreplenishment has not been observed in spectroscopy studies to date.This may be because pathology-induced diffusion barrier thickening isnot uniform across the entire lung in a disease model. Thus, the globalRBC signal replenishment observed by spectroscopy is dominated by thehealthy lung regions where ¹²⁹Xe-blood transfer remains rapid. Toobserve the RBC (211 ppm) signal delay associated with regionalthickening of the diffusion barrier, imaging of the ¹²⁹Xe RBC boundphase can be used.

Imaging ¹²⁹Xe dissolved in lung tissues is significantly morechallenging than imaging ¹²⁹Xe in the airspaces. First, the lung tissuevolume is only about 10% that of the airspace volume (14) and further,the solubility of Xe in lung tissues is only 10% (15, 16), leading to197 ppm and 211 ppm signals that are no more than 1% of the airspacesignal at any given instant. Second, once ¹²⁹Xe is dissolved in lungtissue, the susceptibility-induced transverse relaxation time T₂* isreduced from 20 ms to ˜2 ms. However, understanding this behavior,imaging methods can provide for this relaxation time withsub-millisecond echo times and high bandwidth. Third, ¹²⁹Xe has theability to separately image in the three different frequencycompartments. Such an ability can, for example, elucidate the exchangedynamics, provide better sensitivity as to function, barrier thickness,disease states, drug therapies and the like.

It is believed that, to date, only Swanson and co-workers have succeededin direct imaging of ¹²⁹Xe in the dissolved compartments of the thoraxof the lung by using chemical shift imaging (17). Their use of 30° flipangles and a repetition time of 428 ms ensured that ¹²⁹Xe signal wasgrossly localized to the thorax, but not specifically from the gasexchange regions of the lung. An alternate prior art imaging approachthat retains higher spatial resolution while indirectly probing the gasexchange process is called Xenon polarization Transfer Contrast (XTC).This method uses the attenuation of airspace ¹²⁹Xe signal after RFirradiation of the dissolved phase ¹²⁹Xe frequencies to indirectly map¹²⁹Xe gas exchange between airspace and dissolved phase (18). XTC hasbeen shown to be sensitive to tissue density increases due toatelectasis, for example (13), but it is believed that this methodologycannot, at least presently, distinguish ¹²⁹Xe signal originating fromthe barrier and RBC compartments.

Embodiments of the invention can provide methods for efficientdifferential imaging of ¹²⁹Xe in the airspace, barrier, and RBCcompartments of the lung with 16-fold higher resolution than waspreviously attained (17). Furthermore, as contemplated by someembodiments, directing the imaging to the gas exchange regions of thelung, and separating out barrier and RBC images, can provide specificsensitivity to pulmonary gas exchange. As will be discussed furtherbelow, a successful differentiation of RBC and barrier images wasobtained using a rat model of pulmonary fibrosis in which, at regions ofdiffusion barrier thickening, the RBC image is depleted while thebarrier image continues to substantially if not identically match theairspace image. According to some embodiments of the present invention,¹²⁹Xe imaging methods that evaluate the blood-gas barrier using imagedata from one or more of ¹²⁹Xe MRI barrier and/or RBC images can bereferred to as Xenon Alveolar Capillary Transfer imaging or “XACT”.

To generally understand ¹²⁹Xe signal dynamics in the airspace, barrierand RBC compartments, a simple one-dimensional model of gas diffusion inthe lung can be used. While more complex three-dimensional models meritconsideration (8), a simple model can facilitate an understanding of theprimary factors governing dissolved ¹²⁹Xe signal replenishment,particularly the delayed return of ¹²⁹Xe-RBC signal, an aspectoverlooked in the hyperpolarized ¹²⁹Xe studies performed to date. FIG.1A shows a simple one-dimensional model of gas transfer and signalreplenishment in the barrier tissue and RBCs. FIG. 1A depicts an airspace, pulmonary endothelium, interstitial space, capillary endothelium,plasma, and RBCs. The whole barrier/RBC block can be defined asextending from −L≦x≦L, while the RBC component extends only across thecapillary range −L_(c)≦x≦L_(c) with L_(c)<L. The thickness of thediffusion barrier is then ΔL_(db)=L−L_(c).

FIG. 1B illustrates replenishing of the ¹²⁹Xe magnetization profileacross the entire tissue block including barrier and RBC. FIG. 1Cillustrates replenishing of the barrier signal (197 ppm) for barrierthicknesses ΔL_(db) ranging from 1 μm to 7.5 μm, assumingD_(Xe)=0.33×10⁻⁵ cm²s⁻¹. FIG. 1 D illustrates replenishing of the RBCsignal (211 ppm) for the same range of barrier thickness and constantL_(c)=4 μm. As barrier thickness increases, return of the RBC signalappearance is delayed.

The replenishment of the dissolved ¹²⁹Xe magnetization can be calculatedafter it is destroyed by a frequency-selective 90° rf pulse. It isassumed that the ¹²⁹Xe magnetization in the airspaces (0 ppm) isunaffected by the rf pulse. Immediately after the rf pulse, ¹²⁹Xediffusion begins to re-equilibrate the gaseous and dissolved ¹²⁹Xemagnetizations. A rapidly converging series solution to this type ofsymmetric diffusion problem is provided by Crank (19). The dissolved¹²⁹Xe magnetization profile after replenishing time t, can be expressedby Equation (1):

$\begin{matrix}{{M_{diss}\left( {x,t} \right)} = {\lambda\; M_{air}{\sum\limits_{n = 0}^{\infty}{\left( {- 1} \right)^{n}\left( {{{erfc}\left( \frac{{\left( {{2\; n} + 1} \right)L} + x}{2\sqrt{Dt}} \right)} + {{erfc}\left( \frac{{\left( {{2\; n} + 1} \right)L} - x}{2\sqrt{Dt}} \right)}} \right)}}}} & (1)\end{matrix}$where λ is the solubility of Xe in tissue and M_(air) is the ¹²⁹Xemagnetization in the air space. Here erfc(x)=1-erf(x) is the errorfunction complement with the properties erfc(0)=1, erfc(∞)=0. Severalsimplifying assumptions have been made to preserve the clarity of thediscussion. First, the Xe solubility and diffusion coefficient are thesame throughout the dissolved phase. Second, because the primaryinterest is in signal replenishment on short time scales compared tocapillary transit time (t<300 ms), the effects of blood flow can beignored. Third, the short-time interest period allows the ¹²⁹Xelongitudinal relaxation to be ignored since the shortest known T₁ of¹²⁹Xe in biological fluids is 4 seconds in venous blood (20) and ¹²⁹XeT₁ is >100 s in aqueous environments (21). FIG. 1B depicts the dissolved¹²⁹Xe magnetization replenishment profile. The ¹²⁹Xe magnetization fillsthe dissolved phase from the edges (barrier), with the central portions(RBC) of the capillary regaining magnetization last. After sufficientequilibration time, Dt/L²>>1, a homogeneous ¹²⁹Xe magnetization profileagain exists across the entire tissue block.

The replenishment of ¹²⁹Xe signal from the barrier and RBC compartmentscan be determined by integrating the ¹²⁹Xe magnetization profile overthe regions bounding the 197 ppm and 211 ppm resonances. The 211 ppm RBCresonance is most straightforward to calculate as it results directlyfrom the interaction of ¹²⁹Xe with red blood cells. There is somecontroversy between available in vitro (9, 20, 22) and in vivo data (17)as to whether the 211 ppm peak is purely due to ¹²⁹Xe bound to RBCs orwhether it results from rapid ¹²⁹Xe exchange between plasma and RBCs.However, these issues do not impact the conclusion that the 211 ppmsignal is incontrovertibly associated with ¹²⁹Xe-RBC interaction, but isnoted for completeness. Also, like Mansson et al., it is assumed that¹²⁹Xe in plasma retains its 197 ppm signal and thus the 211 ppm signalresults only from ¹²⁹Xe interacting with the hematocrit, the fraction ofblood composed of RBCs (8). Therefore, it is believed that 211 ppmsignal replenishment is thus obtained according to Equation (2) byintegrating the ¹²⁹Xe magnetization over the capillary dimension L_(c)and scaling by hematocrit fraction Hct which is 0.45-0.50 in healthyrats (23).

$\begin{matrix}{{S_{211}(t)} = {{G_{MR} \cdot {Hct}}{\int_{- L_{c}}^{L_{c}}{{M_{diss}\left( {x,t} \right)}\ {\mathbb{d}x}}}}} & (2)\end{matrix}$G_(MR) is a scaling factor representing the MRI signal chain. The 197ppm signal can thus be expressed along the lines of Equation (3), as theentire dissolved phase integral minus the 211 ppm signal.

$\begin{matrix}{{S_{197}(t)} = {{G_{MR}{\int_{- L}^{L}{{M_{diss}\left( {x,t} \right)}\ {\mathbb{d}x}}}} - {S_{211}(t)}}} & (3)\end{matrix}$The solution to the RBC signal, normalized by the airspace signal S₀ Toabsorb all the MR signal chain scaling constants, can be expressed byEquation (4):

$\begin{matrix}{\frac{\;{S_{211}(t)}}{\; S_{0}} = {\frac{4\;\lambda\;{Hct}\;\sqrt{Dt}}{\; L_{\; A}}{\sum\limits_{n\; = \; 0}^{\;\infty}{\left( {- 1} \right)^{n}\left( {{{\mathbb{i}}\;{{erfc}\left( \frac{{\left( {{2\; n}\; + \; 1} \right)\; L}\; - \; L_{c}}{\;{2\;\sqrt{Dt}}} \right)}} - {{\mathbb{i}}\;{{erfc}\left( \frac{{\left( {{2\; n}\; + \; 1} \right)\; L}\; + \; L_{c}}{\;{2\;\sqrt{Dt}}} \right)}}} \right)}}}} & (4)\end{matrix}$where the airspace signal S₀=M_(air)L_(A), and L_(A) is the lineardimension of an alveolus in this simple one-dimensional model. Here,ierfc(x) is the integral of the error function complement with theproperties ierfc(0)=1/√π and ierfc(∞)=0. One aspect of equation (4) isthat because L_(c)<L, the replenishment of S₂₁₁ can be delayed,depending on the thickness ΔL_(db) of the diffusion barrier separatingthe airspace and the blood cells. For completeness, the integratedintensity of the 197 ppm barrier resonance can be expressed by Equation(5):

$\begin{matrix}{\frac{\;{S_{197}(t)}}{\; S_{0}} = {\left( {\frac{4\;\lambda\;\sqrt{Dt}}{\; L_{A}}{\sum\limits_{n\; = \; 0}^{\;\infty}{\left( {- 1} \right)^{n}\left( {{{\mathbb{i}}\;{{erfc}\left( \frac{{\left( {{2\; n}\; + \; 1} \right)\; L}\; - \; L}{\;{2\;\sqrt{Dt}}} \right)}} - {{\mathbb{i}}\;{{erfc}\left( \frac{{\left( {{2\; n}\; + \; 1} \right)\; L}\; + \; L}{\;{2\;\sqrt{Dt}}} \right)}}} \right)}}} \right) - \frac{S_{211}(t)}{S_{0}}}} & (5)\end{matrix}$Note that S₁₉₇ will begin replenishing immediately after the RF pulse,as fresh ¹²⁹Xe from the air space diffuses in with initial signal growthscaling as √{square root over (Dt)} and surface-to-volume ratio(1/L_(A)) as discussed by Butler (24). FIG. 1C and FIG. 1D show thecalculated replenishment of the barrier and RBC signals for a range ofbarrier thicknesses 1 μm≦ΔL_(db)≦7.5 μm with L_(c) fixed at 4 μm, halfthe diameter of a red blood cell. By way of example, a Xe diffusioncoefficient of 0.33×10⁻⁵ cm²s⁻¹ can be assumed (13) as can a hematocritfraction of 0.5. The delayed replenishment of the RBC resonance when thediffusion barrier ΔL_(db) has thickened beyond 1 μm is readily apparentin FIG. 1D. Note that the expected reduction in RBC signal amplitudeassociated with barrier thickening is much greater than thecorresponding increase in barrier signal. For example, at areplenishment time of 50 ms, the RBC signal is reduced 640% for the 7.5μm barrier vs the 1 μm barrier, while the barrier signal is increased by68%.

To generate images of the dissolved ¹²⁹Xe compartments, the continuousmagnetization replenishment from the gas-phase alveolar reservoir can beexploited. Since dissolved ¹²⁹Xe magnetization recovers with about a ˜40ms time constant in healthy lung, we can apply a large angle pulse,typically about a 90° pulse at roughly that repetition rate. Therepetition rate effectively sets the replenishment timescale and, thus,the diffusion distance scale that can be probed with imaging. SNR can beextended by ˜2 by acquiring image data throughout the breathing cycle.To overcome the exceedingly short T₂* of dissolved phase ¹²⁹Xe (about a1.7 ms estimate), radial imaging can be used (25, 26).

Embodiments of the invention are directed at ways to discriminate ¹²⁹Xein the airspace, barrier, and RBC compartments so that gas transferdynamics can be discerned. Previously, ¹²⁹Xe frequency discriminationwas proposed using chemical shift imaging (CSI) (17). However, for thelung, CSI is unacceptably slow and not amenable to high-resolutionimaging on fast time scales. Frequency-selective rapid Fourier imagingis possible when two resonances are present, as was first demonstratedby Dixon for fat and water separation (27). Thus, imaging two resonancescan be achieved using a frequency selective pulse that excites both the197 and 211 ppm resonances, but not the gas phase resonance at 0 ppm. Aone-point variant of the Dixon technique can be used to obtain separateimages of the 197 ppm and 211 ppm compartments from the real andimaginary components of a single image (28).

Dixon imaging exploits the slight difference in the transverse-planeprecession frequency of two resonances to image them at a predictedphase shift. After the frequency selective rf pulse places the 197 ppmand 211 ppm magnetization into the transverse plane, the 211 ppmmagnetization will precess 330 Hz faster (at 2 T) than the 197 ppmresonance. This phase evolution can be allowed to occur just long enoughfor the 211 ppm spins to accumulate 90° of phase relative to the 197 ppmspins. Then the imaging gradients can be turned on to encode the spatialinformation. The scanner receiver phase is set so that one resonancecontributes to the in-phase image and the other to the out-of-phaseimage. Phase-sensitive imaging allows an image of ¹²⁹Xe replenishment inthe barrier in one channel and in the RBCs in the other channel to beobtained. A phase evolution period that can be used to achieve a 90°phase difference is TE_(90°)=1/4Δf where Δf is the frequency differencebetween the two resonances.

Experimental Overview

All experiments were performed using Fischer 344 rats weighing 170-200 g(Charles River Laboratories, Raleigh, N.C.). Various aspects of the¹²⁹Xe imaging and spectroscopy protocol were initially developed using35 healthy animals. The final protocol consisting of a high-resolution(0.31×0.31 mm²) ventilation image, a phase-sensitive barrier/RBCreplenishment image (1.25×1.25 mm²), and dynamic ¹²⁹Xe spectroscopy wasused to study 9 animals. Seven animals had unilateral fibrosis inducedby bleomycin instillation, one healthy control, and one shaminstillation. Animals were imaged 5-15 days after bleomycininstillation, when inflammatory and early fibrotic changes would presenta thickened diffusion barrier.

The animal protocol was approved by the Institutional Animal Care andUse Committee at Duke University. Interstitial fibrosis was induced byunilateral instillation of bleomycin (29). Rats were anesthetized with46 mg/kg methohexital (Brevital, Monarch Pharma, Bristol, Tenn.) andperorally intubated with an 18 G catheter (Sherwood Medical, Tullamore,Ireland). A curved PE50 catheter was advanced through the endotrachealtube and manipulated to enter the chosen (left or right) pulmonary mainbronchus. While the animal was positioned head-up on a 45° slant board,a solution of bleomycin (Mayne Pharma, Paramus, N.J.) in saline (2.5units/kg) was slowly instilled over a period of 10 seconds. Because theleft lung is significantly smaller than the right, a higherconcentration/lower volume of bleomycin was used for left lunginstillations. For the left lung, 0.07 ml at 6.8 units/ml was instilled,whereas the right lung received 0.2 ml at 2.5 units/ml bleomycin. Shaminstillations were performed similarly using an equivalent volume ofsaline.

¹²⁹Xe Polarization

Polarization of ¹²⁹Xe was accomplished using continuous flow andcryogenic extraction of ¹²⁹Xe (30). A mixture of 1% Xe, 10% N₂ and 89%⁴He (Spectra Gases, Alpha, N.J.) flowed at 1-1.5 SLM through the opticalcell containing optically pumped Rb vapor at a temperature of 180° C.Spin exchange collisions between the Rb valence electrons and ¹²⁹Xetransfer red angular momentum to the ¹²⁹Xe nuclei with an estimated timeconstant of 6 s. Upon exiting the optical cell, hyperpolarized ¹²⁹Xe wasextracted from the other gases by freezing in a 77 K cold trap locatedin a 3 kG magnetic field to preserve solid ¹²⁹Xe polarization (31). Oncea suitable quantity of solid polarized ¹²⁹Xe was produced, it was thawedand captured for delivery. A prototype commercial polarizer(IGI.9600.Xe, Magnetic Imaging Technologies, Durham, N.C.) was used topolarize ˜500 ml of ¹²⁹Xe gas to 8-9% polarization in 45 minutes. Afteraccumulation of ¹²⁹Xe was complete, it was thawed and collected in a 1liter Tedlar bag (Jensen Inert Products, Coral Springs, Fla.) housed ina Plexiglas cylinder. The cylinder was then detached from the polarizerand attached to a hyperpolarized gas compatible ventilator. For allexperiments reported here, xenon was enriched to 83% ¹²⁹Xe. Forspectroscopy studies, about 150 ml of enriched ¹²⁹Xe was polarized anddiluted with 350 ml of N₂.

Animal Preparation—Imaging

Animals were first anesthetized with intraperitoneal (IP) injection of56 mg/kg ketamine (Ketaset, Wyeth, Madison, N.J.) and 2.8 mg/kg diazepam(Abbott Labs, Chicago, Ill.). During imaging anesthesia was maintainedwith periodic injection of ketamine and diazepam at ¼ the initial dose.Rats were perorally intubated using a 16-gauge catheter (SherwoodMedical). The rat was ventilated in a prone position at a rate of 60breaths/min and a tidal volume of 2.0 ml using a constant volumehyperpolarized gas ventilator as described by Chen et al., (32). During¹²⁹Xe imaging, breathing gas was switched from air to a mixture of 75%HP xenon mixed with 25% O₂ To achieve a tidal volume of 2 ml. A singlebreath was characterized by a 300 ms inhalation, 200 ms breath-hold, anda 500 ms passive exhalation. The ventilator triggered the MRI scanner atthe end of inspiration for high-resolution airspace imaging during thebreath-hold. Airway pressure, temperature, and ECG were monitoredcontinuously and body temperature was controlled by warm air circulatingthrough the bore of the magnet using feedback from a rectal temperatureprobe.

Imaging and Spectroscopy Hardware

All images and spectra were acquired on a 2.0 T horizontal 30 cm clearbore magnet (Oxford Instruments, Oxford, UK) with shielded gradients (18G/cm), controlled by a GE EXCITE 11.0 console (GE Healthcare, Milwaukee,Wis.). The 64 MHz rf system was made to operate at the ¹²⁹Xe frequencyof 23.639 MHz using an up-down converter (Cummings Electronics Labs,North Andover, Mass.). A linear birdcage rf coil (7 cm diameter, 8 cmlong) operating at 23.639 MHz was used for imaging. An integratedTransmit/Receive switch and 31 dB gain preamplifier (Nova Medical,Wilmington, Mass.) was interfaced between the coil and scanner.

Airspace ¹²⁹Xe Imaging Procedure

Airspace ¹²⁹Xe images were acquired using a radial encoding sequencethat has been described previously (33). Images were acquired withoutslice selection, 4 cm FOV, 8 kHz bandwidth, and reconstructed on a128×128 matrix with a Nyquist resolution limit of 0.31×0.31 mm²in-plane. K-space was filled using 400 radial projections, 10 views perbreath, TR=20 ms, thus employing 40 breaths (40 s) to complete theimage. For each view n in a breath, a variable flip angle scheme,calculated according to α_(n)=arctan (1/√10−n) (34), was employed toboth use the available magnetization most efficiently and to generateimages that distinguish the major airways from parenchyma. All imagingand spectroscopy employed a truncated sinc excitation pulse with onecentral lobe and one side lobe on either side. To avoid contaminatingthe airspace image with ¹²⁹Xe signal from the barrier and RBCcompartments, a total pulse length of 1.2 ms with frequency centered ongas-phase ¹²⁹Xe (0 ppm) was used.

Dynamic Spectroscopy Procedure

Dynamic spectra measuring ¹²⁹Xe replenishment in the entire lung wereacquired with repetition time (TR) values ranging from 11 To 200 ms. 90°excitation pulses of 1.05 ms duration centered at 204 ppm were used tosimultaneously read and destroy the ¹²⁹Xe magnetization in the 197 and211 ppm compartments. 256 points per spectrum were acquired at abandwidth of 15 kHz, (32 μs dwell time). The bandwidth of the 1.05 mssinc pulse excited the barrier and RBC resonances with a 90° flip whileproviding a 0.15° flip to the airspace ¹²⁹Xe to provide the 0 ppmreference frequency. Spectra were recorded using TR values of 11, 15,20, 30, 40, 50, 75, 100, 125, 150, 175, and 200 ms. For each TR value,the maximum number of spectra was acquired during the 200 ms breath-holdand averaged over 5 breaths. The first spectrum of each breath-holdperiod was discarded, since it resulted from 800 ms of replenishmentrather than the specified TR period. The raw data for each spectrum wasline broadened (25 Hz), baseline corrected, Fourier transformed and fitusing routines written in the MATLAB environment (The MathWorks, Natick,Mass.). Curve fitting of the real and imaginary spectra prior to phasecorrection allowed extraction of the amplitudes, frequencies,line-widths, and phases of each resonance. This information was used toset the receiver frequency and phase to ensure that, in subsequentbarrier/RBC imaging, the imaginary channel contained the ¹²⁹Xe-barrierimage and the real channel contained the ¹²⁹Xe-RBC image.

Barrier/RB C ¹²⁹Xe Replenishment Imaging Procedure

Non-slice-selective ¹²⁹Xe images of the barrier and RBC compartmentswere acquired using 2D radial projection encoding with a TR of 50 ms, a90° flip angle, an FOV of 8 cm, and a grid of 64×64 for a Nyquistresolution limit of 1.25×1.25 mm². The combination of a 90° flip angleand a TR of 50 ms made the images sensitive to diffusion barrierthickening on the order of 5 μm. A 1.2 ms sinc pulse centered on the 211ppm blood resonance was used to excite only the 197 and 211 ppmresonances, and not the airspace ¹²⁹Xe. This minimum pulse durationyielding no detectable 0 ppm signal was determined using phantomscontaining only gas-phase hyperpolarized ¹²⁹Xe. An imaging bandwidth of15 kHz ensured that radial encoding lasted roughly 2 ms, on the sameorder as T₂* decay. K-space was overfilled using 2400 frames acquiredthroughout the ventilation cycle to maximize signal averaging from thebarrier/RBC compartments. Thus, the dissolved image used about 120breaths (2 min) to acquire. To discriminate the 197 and 211 ppmresonance, the echo time was calculated according to TE₉₀=1/4Δf. At 2Tesla one can calculate TE₉₀=755 μs for the 211 ppm RBC and 197 ppmbarrier resonances. Empirically, however, the echo time TE₉₀ can bedetermined using whole-lung spectroscopy and an optimal value was foundto be closer to 860 μs-940 μs, varying slightly in each animal. Theslight discrepancy between calculated and empirical echo times is notfully understood, but may be explained by the long duration of the rfpulse, compartmental exchange of ¹²⁹Xe during the rf pulse, or fieldinhomogeneity over the entire lung. Phase-sensitive images werereconstructed such that the real image displayed ¹²⁹Xe in the 211 ppmRBC compartment and the imaginary image contained the 197 ppm barrierimage.

Histology

After imaging, rats were sacrificed with a lethal dose of pentobarbital(Nembutal, Abbott Labs, Chicago, Ill.). Lungs were instilled with 10%formalin at 25 cm H₂O for 30 minutes and thereafter stored in 10%formalin. The lungs were processed for conventional histology andstained with H&E stain and Masson's Trichrome for collagen. Slides wereevaluated to look for thickening of the alveolar septa, qualitativecorrespondence of location and extent of the injury with imaging, and toconfirm that the contralateral lung was uninjured. A semi-quantitativemeasure of the fraction of each lung lobe affected by the bleomycin wasdetermined by visual inspection.

Image Analysis

Images of ¹²⁹Xe in the airspace, barrier, and RBCs were analyzed usingan automated routine written in MATLAB (The MathWorks, Natick, Mass.) toquantify the number of image pixels containing signal. Pixels wereconsidered “on” if they exceeded two times the mean of the backgroundnoise. Signal to noise for each image was calculated by dividing themean value of all the pixels above threshold with mean backgroundsignal. The unilaterally induced injury made it fruitful to analyze leftand right lungs separately by manually drawing a border between the twolobes of the ventilation image. Because images were two-dimensional, theportion of the right accessory lobe that overlaps with the left lung wasunavoidably counted in the left lung. In each lung the ratio ofsignal-containing pixels in RBC and barrier images (RBC/barrier ratio)was taken as the primary measure of gas transfer efficiency.

Spectroscopy Analysis

The 211 and 197 ppm signal integrals derived from dynamic whole-lungspectroscopy were fit to equations (4) and (5) governing theirreplenishment. Because the injury was non-uniform and spectroscopysignals originate from the entire lung, any regional delay in RBC signaldue to barrier thickening is obscured by the healthy regions of the lungwhere RBC signal replenishment remains rapid. Thus, the shape of eachreplenishment curve was qualitatively indistinguishable between healthyand treated animals and curve fitting could not extract independentvalues for the diffusion coefficient D, and length parameters L, andL_(c). Instead, D was held fixed at 0.33×10⁻⁵ cm²s⁻¹ and L, L_(c), andthe saturation amplitudes were extracted. However, regions of RBC signaldelay did result in an overall reduction in the 211 ppm signal integralrelative to the 197 ppm signal. Thus, from the amplitudes of fittedcurves, the ratio of RBC/barrier integral could be calculated for eachanimal and used as a measure of gas transfer efficiency.

FIGS. 2A-2F shows images of ¹²⁹Xe in the airspaces, barrier and RBC.FIGS. 2A-2C correspond to a left lung sham-instilled rat (#2) and FIG.2D-2F correspond to a rat with left lung fibrosis (#5) imaged 11 dayspost-bleomycin instillation. Most notable is the nearly complete absenceof ¹²⁹Xe RBC replenishment in the injured lung of the diseased animal(FIG. 2F), whereas barrier replenishment appears closely matched to theairspace image (see barrier images in FIGS. 2B and 2E that closely matchthe corresponding air space images in FIGS. 2A and 2D).

The absence of signal indicates that ¹²⁹Xe does not reach the RBCs onthe 50 ms image acquisition time scale, likely resulting from increaseddiffusion barrier thickness. The matching of barrier image intensitywith airspace image intensity was noted in all studies. The mismatchingof RBC replenishment with barrier replenishment was a hallmark findingin all injured lungs. Absence of RBC replenishment on the 50 ms imagingtime-scale is consistent with the predictions of the simple model andsuggests thickening of the diffusion barrier beyond its normal thicknessof 1 μm to greater than 5 μm (assuming D=0.33×10⁵ cm²s⁻¹). Note alsothat the volume of the left fibrotic lung is reduced on the airspaceimage (FIG. 2D), while the right lung exhibits compensatoryhyperinflation. This reduction in volume of the injured lung was notedin all 7 bleomycin treated animals.

H&E stained sections from a control left lung of rat #8 (FIG. 3A) andthe bleomycin instilled left lung of rat #5 (FIG. 3B). Thickenedalveolar septa are clearly visible in the treated lung compared to thecontrol lung. Such thickening was observed throughout the injured lungof this rat and is representative of what could be observed in theinjured lungs of all the treated rats. Masson's stained slides showedsimilar thickening patterns and reflected increased collagen deposition,particularly at longer post-instillation times. The histologicalfindings and RBC/barrier mismatch found in the images are summarized inTable 1.

TABLE 1 HISTOLOGY Animal/Status RBC/Barrier Histology Findings IDInjury/days Mismatch Left Cranial Middle Caudal Accessory 1 control NoneNA NA NA NA NA 2 LL 15 Sham None NA NA NA NA NA 3 LL 15 LL apex, base30% NA NA NA NA 4 LL 13 LL apex, base, medial 60%  0%  0%  0%  0% 5 LL11LL apex, base 50%  0%  0%  0%  0% 6 LL 8 LL apex, base 40% NA NA NA NA 7RL 15 RL base  0% 25% 30% 50% 40% 8 RL 7 RL apex, base  0% 40% 40% 60%NA 9 RL 5 RL base, LL medial  5%  5% 40% 75% 40%Regions of RBC/barrier mismatch were always associated with findings ofinjury on histology. In one right-lung instilled animal (#9), a smallregion of RBC/barrier mismatch (2×2 pixels) was noted in the medialapical region of the left lung. Histological examination of the leftlung confirmed the presence of a small region of injury, which hadpresumably resulted from an incidental drop of bleomycin contaminationduring right lung instillation. This finding provides an early indicatorof the sensitivity of the technique.

Table 1 is a summary of RBC/barrier mismatch seen with ¹²⁹Xe imagingcompared to histological findings in each lung lobe. The left lungconsists of one lobe, whereas the right lung contains the cranial,middle, caudal, and accessory lobes. Note that in each image withRBC/barrier signal mismatch, corresponding injury was found in thatregion of the lung on histology. Histological sections for each lobewere evaluated by visual inspection to provide a semi-quantitativemeasure of the injured fraction. Some regions of injury found onhistology were not immediately apparent from RBC/barrier mismatch. Thoseregions of injury could have been so consolidated that they were nolonger ventilated and thus exhibit no signal in any of the compartments.

The close matching of barrier images with the airspace images isillustrated in FIG. 4 where the pixel counts from the barrier and RBCimages are plotted against the airspace pixel counts for the right andleft lungs of all animals. Barrier pixel counts closely matched theairspace pixel counts in both control and injured lungs with R²=0.93,and a slope of 0.88±0.02 represented by the regression line. The slopeof less than unity results from smaller average lung inflation duringdissolved phase imaging, which was performed over the entire breathingcycle, versus airspace imaging which was performed at full inspiration.The observed matching is consistent with the fact that the barriercompartment is adjacent to the airspace compartment.

FIG. 4 is the ratio of normalized ¹²⁹Xe pixel count in barrier and RBCimages versus pixel count in the airspace images in each lung. Pixelcounts were separated by right and left lung to take into accountreduced lung volume in injured lungs and to allow one lung to serve as acontrol. As noted above, a strong correlation (R²=0.93) is seen betweenbarrier and airspace pixel counts (as would be expected since thesecompartments are adjacent to one another). The regression line is a fitto all the barrier pixel counts in injured and uninjured lungs. Alsoshown are the RBC pixel counts for control and injured lungs. In controllungs, the RBC pixel count correlated well with airspace counts(R²=0.83), and as expected, in injured lungs it correlated poorly(R2=0.14). Note that 5 of the 7 injured lung RBC pixel counts fall farbelow the regression line and thus represent severe mismatch. In two ofthe animals with right lung injury (#7 and #9) no measurable mismatchwas observed. In these animals it appears that the bleomycininstillation created a complete ventilation block in the region ofinjury and thus likely obscured any RBC/barrier mismatch by preventing¹²⁹Xe from reaching the area.

FIG. 5 shows the dynamic spectroscopy of ¹²⁹Xe replenishment into thebarrier and RBC compartments (dynamic spectra and corresponding fit)covering the entire lung of both a healthy control (#1) animal (FIGS.5A, 5B) and right-lung-injured (#9) rat (FIGS. 5C, 5D), 5 dayspost-instillation. Note that the ratio of RBC/barrier signal atsaturation is markedly diminished in the injured animal (FIG. 5D) versusthe control animal (FIG. 5B).

While the shapes of the replenishment curves (and thus values of L andL_(c) derived from curve fitting) were indistinguishable between thehealthy and treated rat, the ratio of saturation RBC signal to barriersignal was dramatically different. The control animal showed anRBC/barrier=0.92 versus the injured animal with RBC/barrier=0.57. Thus,the RBC/barrier ratio derived from spectroscopy may be sensitive toalveolar-capillary gas transfer, though it lacks the spatial specificityof imaging. For completeness, the values of L and L_(c) derived fromcurve fitting of data from all rats were L=5.5±0.4, L_(c)=5.1±0.6assuming D=0.33×10⁻⁵ cm²s⁻¹, which are plausible values for healthylung.

A notable feature of the XACT imaging technique is that regions showingbarrier intensity, but no RBC intensity (RBC/barrier mismatch),corresponded to regions of barrier thickening found on histology. Thus,RBC/barrier ratios represent a simple and useful means of quantifyingand comparing degrees of injury from the images. Table 2 summarizes theRBC/barrier ratios derived from imaging and spectroscopy in all theanimals studied. The image-derived RBC/barrier ratio from the injuredlungs was 0.59±0.24, which was significantly reduced (p=0.002) from theRBC/barrier ratio of 0.95±0.10 in the control lungs. Thespectroscopy-derived RBC/barrier ratio was 0.69±0.12, which was alsosignificantly reduced (p=0.02) compared to the RBC/barrier ratiodetermined from 5 healthy control rats (not shown in table) with a ratioof 0.87±0.14. It is postulated that there should be correspondencebetween the RBC/barrier ratios derived from the images and spectra in agiven animal, since spectra simply represent a collapse of thephase-sensitive image into its spectral components. This correspondenceappears to exist in most of the rats studied. However, for the two ratswith right lung injury and ventilation blockage (#7 and #9), the wholelung image-derived RBC/barrier ratio appeared normal whereas thespectroscopy-derived ratio was markedly reduced. The discrepancy inthese two animals between imaging and spectroscopy is not fullyunderstood, but could be a result of spectroscopy being performed atfull inspiration where capillary blood volume could be reduced ininjured areas.

TABLE 2 RATIOS Animal/Status RBC/Barrier Ratios ID Injury/Days Inj LungCtrl Lung Whole Spectra 1 control NA 0.95 0.96 0.92 2 LL 15 Sham 0.880.94 0.92 0.84 3 LL 15 0.51 0.88 0.70 0.81 4 LL 13 0.55 1.02 0.85 0.78 5LL11 0.45 1.06 0.83 0.83 6 LL 8 0.25 0.85 0.65 0.67 7 RL 15 0.89 1.010.95 0.69 8 RL 7 0.56 0.80 0.71 0.51 9 RL 5 0.93 1.03 0.99 0.57

Table 2 provides a summary of RBC/barrier ratios derived from imagingand spectroscopy. The image-derived RBC/barrier ratio is significantlyreduced (p=0.002) in all injured lungs relative to control lungs.Similarly, the mean spectroscopy-derived RBC/barrier ratio of 0.69±0.12in treated animals is significantly reduced (p=0.02) compared to a valueof 0.87±0.14 found in 5 healthy controls (not shown in table). TheRBC/barrier ratios calculated from the images of both lungs comparerelatively well with those determined by spectroscopy with the exceptionof two animals. In those two right lung injured animals (#7 and #9),bleomycin injury appeared to block ventilation, thus preventing regionsof RBC/barrier mismatch from contributing to the images.

The barrier/RBC images result from dissolved-phase ¹²⁹Xe and not mereairspace ¹²⁹Xe signal contamination. First, it is noted that abarrier/RBC image SNR (6.8±2) and resolution (1.25×1.25 m²) versus airspace image SNR (9.1±2) and resolution (0.31×0.31 mm²) are consistentwith known solubility and tissue density differences. From the airspaceimages, dissolved images lose a factor of 100 in each of the barrier/RBCcompartments and a factor of √2 due to higher bandwidth. Signal gains ofa factor 3 due to increased flip angle, and √{square root over(2400/400)} from signal averaging leave a barrier and RBC signalstrength of about 1/20 of the airspace, which when spread out spatiallysuggests a possible image resolution of 1.3×1.3 mm²—which is what hasbeen achieved. Second, the absence of the major airways in thebarrier/RBC images is noted, which is consistent with the expectationthat gas exchange is most prominent in the alveoli (18). Third, the gasphase signal is nearly 5 kHz away from the barrier/RBC resonances, wherethe scanner is tuned. In radial imaging, such off-resonant artifactsmanifest themselves as a halo around the primary image (25), and no suchhalo is observed.

The 211 ppm and 197 ppm compartments have been substantially completelyseparated by the imaging methods described. Evidence of this separationis the clearly reduced ¹²⁹Xe RBC signal in the injured lungs, anobservation that is entirely consistent with predictions based on thedisease model. Meanwhile, the barrier compartment images always matchedclosely to the airspace images as expected given their adjacentlocation. Further evidence that the RBC/barrier compartments areseparated stems from the reasonably good correlation (R²=0.83) betweenRBC/barrier ratios derived from imaging versus the same ratio derivedfrom spectroscopy in 7 of the 9 images (excluding two animals withblocked ventilation). One cannot rule out some residual overlap of theRBC/barrier resonances in the images. For example, significant RBC imageintensity is not observed in the right accessory lobe of the uninjuredlungs. This lobe, which curls around the heart, likely experiences aslightly reduced B₀ field due to the large blood volume of the heart,thus retarding the RBC signal phase in this lobe back to the barrierchannel. A possible correction for these undesired phase shifts is touse phase-sensitive images of ¹²⁹Xe in the airspace to create a fieldmap to correct these distortions as will be discussed further below.Since airspace images are derived from just the 0 ppm resonance, anyphase shifts are only attributable to B₀ variations.

It is not believed that the reduced RBC signals are the result ofshortened ¹²⁹Xe relaxation times T₁, T₂ or T₂* post injury rather thanthe proposed diffusion barrier thickening. To cause the reducedintensity in the RBC images, a T₁ relaxation time on the order 50 ms isused. While in vivo ¹²⁹Xe relaxation times less than 4 s have not beenreported in the literature, such rapid relaxation could be caused eitherby a dramatically increased concentration of paramagnetic centers orlengthened correlation times resulting from reduced ¹²⁹Xe mobility inregions of injury. If by some means an excess of free radicals occurredin regions of injury, this would likely affect both the RBC and barriercompartments equally. Conceivably, ¹²⁹Xe binding to collagen depositsassociated with fibrosis could result in reduced ¹²⁹Xe mobilityaccompanied by a reduction in both T₁ and T₂, which could result insignal attenuation. However, such relaxation would affect the barriercompartment, not the RBC compartment, opposite from the effect requiredto explain our observations.

It is not believed that the RBC/barrier mismatch effect could bepartially caused by reduced capillary density or blood volume ratherthan increased diffusion barrier thickness. However, such a possibilityis not definitively excluded as a contribution from capillarydestruction based on the data. Stained sections do show areas of lungthat are so severely injured as to be fully consolidated, lack alveoli,airways, and capillaries and, thus, would not contribute ¹²⁹Xe signal inany of the compartments. Other areas of injured lung clearly have intactalveoli with thickened alveolar septa and also have capillaries andRBCs. Although it is possible that a reduction of blood volume in theinjured lung may contribute to the absent RBC signal, the overridingfactor appears to be the diffusional delay due to interstitialthickening.

Dynamic spectroscopy also appears to be sensitive to gas exchangeefficiency, although the effect does not appear as yet to be as powerfulas imaging. However, the limited gas usage and simplicity ofspectroscopy merit its continued consideration. A useful extension ofspectroscopy may be to acquire airspace ¹²⁹Xe signals with well definedflip angle which could then be used to quantify the increased 197 ppmand decreased 211 ppm signal intensities relative to controls. Wholelung spectroscopy may not directly validate the model of RBC signaldelay, since any regional delay is averaged out by healthy lung regions.However, with increased hyperpolarized ¹²⁹Xe production, dissolved ¹²⁹Xeimages could be generated at multiple TR values, effectively creatinglocalized dynamic spectroscopic information which would allow regionalcurve fitting of the 197 and 211 ppm pixel intensities to equations 4and 5 To extract meaningful values for L, L_(c) and D on apixel-by-pixel basis.

As shown in FIG. 1D, a thickening of the barrier by 6.5 μm can createabout a 600% attenuation in the RBC replenishment (at 50 ms TR), whileonly reducing a 75 μm diameter rat alveolus to roughly 62 μm and likelyreducing ADC (35, 36) by less than 20%. Similarly, the ability todistinguish barrier and RBC could make XACT more sensitive that priorart techniques to interstitial thickening. Since the XTC (13, 18)contrast comes from the total increase in tissue volume, the sameexample of 6.5 μm thickening would cause a roughly 60% increase in theXTC effect.

XACT is likely to be more sensitive to either ADC imaging or XTC imagingto changes in barrier thickness. In the past, pulmonary fibrosis in theclinical setting is often detected and monitored using high-resolutionCT (38), although significant challenges remain (39) and more invasivesurgical lung biopsy remains the gold standard (40). Embodiments of thepresent invention provide methods that are sensitive to micron-scalechanges in the blood/gas barrier thickness and thus may provideincreased sensitivity and specificity compared to CT, particularly inearly disease. Furthermore, the substantially non-invasive nature of themethod should allow for monitoring of patients and their response totherapeutic intervention.

Embodiments of the invention can be used to generate 3D clinical images.To obtain the 3-D images larger volumes of ¹²⁹Xe gas relative to thoseused in the rat evaluations and/or higher polarization levels can beused. Also, a lower diffusion coefficient for the barrier/RBC resonancesmay allow more efficient multi-echo sequences to be used in order toextract more signal from the limited dissolved ¹²⁹Xe magnetization,although ¹²⁹Xe exchange may hamper this prospect. Third, furtherdiscrimination of the barrier/RBC resonances can be achieved bycorrecting these images using a field map generated from thesingle-resonance airspace ¹²⁹Xe image. This technical development canfacilitate clinical application to subjects where the increased imagingvolume may lead to larger phase distortions.

Although in small animals, images are routinely acquired over multiplebreaths, a human subject can inhale ˜1 liter of ¹²⁹Xe in a singlebreath, enabling equivalent anatomical resolution images to begenerated. To image gas-exchange in 3D, projection-reconstructionimaging (projection encoding in 3D) can be used.Projection-reconstruction imaging in 2D of dissolved ¹²⁹Xe replenishmenthas required relatively small volumes of hyperpolarized ¹²⁹Xe (150 ml).To overcome the very short transverse relaxation time T₂* of dissolved¹²⁹Xe (˜1.7 ms), projection reconstruction (PR) imaging can be used(41). PR is well suited to short T2* environments due to its ultra-shortecho times. Furthermore, the single-point Dixon technique used to createseparate images of ¹²⁹Xe in the barrier vs. the RBCs can operate with anecho time of only ˜800 μs. Thus, for 3D imaging, PR sampling of Fourierspace can be used.

Like 2DPR, 3DPR is capable of 800 μs echo times to create 90° separationbetween the 197 ppm and 211 ppm resonances. 3D projection encoding usesmore radial projections than 2D projection encoding, and thus may needadditional ¹²⁹Xe gas. To facilitate 3D sampling for ¹²⁹Xe gas exchange,imaging 3D projection encoding with phase-sensitive reconstruction canbe used and also, an efficient 3D k-space trajectory model can be used,reducing the number of radial views.

An example of a conventional 3D projection trajectory is shown in FIG.10A. FIG. 10B illustrates a more efficient 3D trajectory. Thistrajectory was developed by Song, et al. (42) and requires 9329 framesto produce a 64×64×16 image matrix, a 30% reduction in the number offrames required by the conventional 3DPR code. The frames can besupplied by about 750 ml of hyperpolarized ¹²⁹Xe or about 466 breaths.This efficient reconstruction approach can eliminate the typicalre-gridding of the k-space data to a Cartesian space. Instead, a direct,non-uniform Fourier transform is used which removes constraints on thek-space trajectory and makes the efficiency possible.

Improved RBC/Barrier separation can be obtained. ¹²⁹Xe signal in the 197ppm barrier compartment and the 211 ppm RBC compartment are, to firstorder, well-separated on phase-sensitive imaging. As discussed above, adisease model has shown to increase the thickness of the blood/gasbarrier and, as predicted, the RBC uptake image (211 ppm) showed regionsof signal deficit, whereas the barrier uptake image (197 ppm) closelymatched the air space image. Also, the whole-lung ratio of RBC/barrieruptake calculated from imaging correlated well (R²=0.64) with theRBC/barrier uptake ratio from dynamic spectroscopy.

However, the RBC/barrier separation is not perfect. One notable exampleis the absence of the right accessory lobe from the RBC uptake imageseven in control rats. This lobe, which curls around the front of theheart, experiences a slightly reduced B₀ due to the high susceptibilityof blood in the heart compared to lung tissue. While planned extensionsto 3D imaging will eliminate some of the distortions, methods can beused to correct for them. This correction may be useful for extension toclinical imaging.

As discussed above, to separate RBC/barrier uptake imaging, a 1-pointDixon technique has been used. This simple implementation of the Dixontechnique assumes that the frequency variation during the “echo time” isonly dependent on the chemical shift difference between the two species.This over-simplification assumes essentially perfect B₀ homogeneity overthe entire sample. Particularly in the lung, such perfection istypically unattainable. For fat/water separation, numerous variants ofthe Dixon technique (2-point Dixon [43], 3-point Dixon [41]) haveemerged to try to de-convolute the desired chemical shifts fromunintended phase shifts arising from B₀ field distortions.

Unfortunately, these more sophisticated versions of the Dixon techniqueare not suitable for application in the short T₂* environment of thelung because all require images made at several increasingly long echotimes. In the lung, where T₂* is only 1.7 ms at a 2 T field, theattenuation at the second echo time is too great. Thus, a 1-point Dixontechnique with ultra-short echo time is better suited for theapplication. Fortunately, B₀ inhomogeneity corrections can be made byusing the ability to make an entirely separate image of ¹²⁹Xe in theair-space. Since the airspace image comes from only one ¹²⁹Xe resonance,phase differences can be attributed to B₀ fluctuations.

In some embodiments, to correct the RBC/barrier images, an electronicmap or maps of air space phase variation can be generated usingphase-sensitive ¹²⁹Xe ventilation images. The phase map can beconstructed from the ratio of imaginary to real image channels accordingto tan(φ(x,y))=1M(x,y)/RE(x,y). A preliminary version of such a map,generated from a non-slice selective image, is displayed in FIG. 11C.Note the accessory lobe has a −40° phase shift, while the trachea has+50° phase shift. The phase map may be in color as indicated by thegraduated color chart (shown in black and white) indicating phasevariation. A visual map need not be created; only the spatial and phasedata can be directly applied to correct the dissolved phase ¹²⁹Xe imagedata. FIG. 11A illustrates a real channel image. FIG. 11B illustrates animaginary channel image. FIG. 11C is the phase map generated from theairspace image. The phase variations in the image map are due to B₀inhomogeneity and can be used to correct barrier/RBC ¹²⁹Xe images.

B₀ maps with 3D projection encoding, or a series of 2D slices (T₂* issufficiently long for gas phase ¹²⁹Xe to use slice selective pulses),can be generated. Data used to generate the RBC/barrier images can becorrected using either the raw phase map, or if unduly noisy, phasevariation can be fit to a smoothed function. The resolution of the phasemaps must be only as high as the dissolved phase image resolution,anticipated at 1×1×5 mm³ for rats and about 10×10×10 for humans. Thus,generating them need not consume undue amounts of the hyperpolarized¹²⁹Xe.

For dissolved phase imaging, the MRI receiver phase is set viawhole-lung spectroscopy, such that the 211 ppm RBC resonance correspondsto the real channel, and the 197 ppm resonance lags 90° behind in thenegative imaginary channel (FIG. 12A). Thus, a simple one-to-onecorrespondence of the real channel to the 211 ppm, and imaginary channelto 197 ppm resonance can be assumed along the lines of Equation (6):

$\begin{matrix}{\begin{pmatrix}S_{211} \\S_{197}\end{pmatrix} = {\begin{pmatrix}1 & 0 \\0 & {- 1}\end{pmatrix}\begin{pmatrix}{Re} \\{Im}\end{pmatrix}}} & \lbrack 6\rbrack\end{matrix}$In fact, when phase variations φ due to B₀ distortion are taken intoaccount (FIG. 12B), the mapping function becomes as expressed inEquation (7):

$\begin{matrix}{\begin{pmatrix}S_{211} \\S_{197}\end{pmatrix} = {\begin{pmatrix}{\cos\;\phi} & {\sin\;\phi} \\{\sin\;\phi} & {{- \cos}\;\phi}\end{pmatrix}\begin{pmatrix}{Re} \\{Im}\end{pmatrix}}} & \lbrack 7\rbrack\end{matrix}$

In initial ¹²⁹Xe uptake imaging studies, −40° phase shifts have causedthe right accessory lobe to disappear from the RBC image. Because the197 ppm resonance is captured in the negative imaginary channel, its−40° shift subtracts from the real channel. The correction schemedescribed should eliminate such undesired mixing and will be mosteffective if the phase shifts fall between −180° and 180°, althoughunwrapping of larger phase-shifts is possible [63]. Thenon-slice-selective images exhibit only ±40° phase shifts and furtherreductions can be expected when thinner slices are used. The relativelysmall phase shifts, even in the hostile lung environment, are aparadoxical benefit of the small ¹²⁹Xe gyromagnetic ratio.

FIGS. 13A and 13B are sets of images taken of a healthy rat at variousTR values. FIG. 13A are barrier images taken (from left to right) atTR=10, 15, 25, 50 ms. The images in FIG. 13B are of the RBC and weretaken at the same TR intervals. By acquiring dissolved ¹²⁹Xe images atmultiple repetition times, typically at least three, and more typicallybetween 3-5 different TR times, with TR values between about 10 ms toabout 60 ms (for example, 10, 20, 30, 40, 50 ms), sufficient data can beobtained to curve-fit the signal replenishment on a pixel-by-pixel basisto extract quantitative measures of barrier thickness and/or ¹²⁹Xediffusion coefficient.

FIG. 6 is a flow chart of exemplary operations that may be used to carryout embodiments of the present invention. As shown, dissolved phase¹²⁹Xe signal data of the alveolar capillary barrier are obtained (block10). Similarly, dissolved phase ¹²⁹Xe signal data of red blood cellswithin the gas exchange regions of the lung (proximate the barrier) areobtained (block 20). Alveolar-capillary gas transfer can be assessedbased on the obtained barrier and RBC signal data (block 30).

The respective data can be used to generate an MRI image of the barrier(block 11) and MRI image of the RBCs (block 21). The two images can becompared to evaluate a barrier injury, disease or therapy (i.e.,thickness or thinning) and/or function. A ¹²⁹Xe airspace image can beobtained to generate a phase variation map and data from the phasevariation map can be used to correct B₀ inhomogeneity induced phasevariations in the RBC and barrier images (block 35).

Once the ¹²⁹Xe gas is dissolved, it no longer has such a massivediffusion coefficient. So one may elect to employ pulse sequences likespin-echo imaging instead of radial imaging. A 64×64 spin echo image canbe acquired using only 64 rf excitations (vs 200 with radial imaging).Also, multiple spin echoes can be employed to improve SNR.

Alternatively, or additionally, the data can comprise NMR barrierspectra (block 12) and RBC spectra (block 22). A ratio of the RBC peaksize to barrier peak size can be determined and used to assess gastransfer and/or lung health (block 32). An airspace ¹²⁹Xe NMR spectracan also be obtained and used to calibrate the RBC and/or barrier peaks(block 33).

FIG. 7 is a flow chart of steps that can be used to carry out certainembodiments of the invention. As shown, a 90 degree flip angleexcitation pulse is transmitted with a pulse repetition time TR betweenabout 40-60 ms. ¹²⁹Xe dissolved phase images of the barrier and of theRBC are obtained, (block 45) and (block 50), respectively, based on theexcitation of the pulse. The two images can be generated using the sameexcitation (resonance) frequency by separating image signal data using a1-point Dixon technique (block 47). Alveolar-capillary transfer and/orbarrier status based on the obtained images (block 55).

It is noted that although a 1-point Dixon technique has been used todecompile or separate the image signal data as discussed herein, otherDixon or signal processing techniques, modified to work with the shorthyperpolarized xenon relaxation times (the signal can decay in a fewmilliseconds) in the lung may be used, such as, for example a modified2-point Dixon.

FIG. 8 is a schematic diagram of an MRI scanner 100 with asuperconducting magnet 150, a gradient system 160 and an RF coil 170that communicates with an RF amplifier (not shown) associated with theMRI scanner as is well known to those of skill in the art. As alsoshown, the MRI scanner includes a multi-channel receiver 105 withchannel 1 103, which can be the real channel, and channel 2 104, whichcan be the imaginary channel. Signal from the RF coil 170 may betransmitted to the receiver 105 via a cable (typically a BNC cable)where the signal can be decomposed into the two channels 103, 104. TheMRI scanner 100 also includes a controller 101, a frequency adjustorcircuit 102 that can tune the MRI scanner to generate a desired RFexcitation frequency, and a display 110. The display 110 may be local orremote. The display 110 can be configured to display the RBC and barrierimages substantially concurrently, or as an image that considers imagedata from both (and magnetic field inhomogeniety correction asappropriate), to provide a 3-D image of the gas-exchange regions of thelung.

The MRI scanner 100 can also include an XATC operational module 120,which can programmatically communicate with the frequency adjustorcircuit 102 and receiver 105 to electronically (automatically) switchoperational modes, frequencies, phases and/or electronically direct theexcitation and acquisition of appropriate signals, and generate the XATCimages and/or NMR spectra evaluation according to some embodiments ofthe invention. See description above for the frequency of gas (MHz) withthe dissolved phase ¹²⁹Xe shifted higher in Hz according to the magneticfield strength of the system.

In some embodiments, the module 120 can be configured to form a curvefit to extract phases and frequencies of the 197 ppm and 211 ppm peaksthen automatically set channel 1 (the real channel) so that the RBCimage comes from channel 1 103 and the barrier image comes from channel2 104 (the imaginary channel), although the reverse may also be used.The automated software routine can take a few spectra, thenautomatically set the scanner frequency and phase to XACT imaging andapply the desired excitation pulse and TR times. The module 120 may alsobe configured to generate the images using radial imaging and/or spinecho imaging noted above. The module 120 can be configured to generate aphase variation map using image data of a ¹²⁹Xe ventilation image of thelung and programmatically electronically correct phase errors in RBC andbarrier image data.

In some embodiments, the MRI scanner 100 can be configured to obtainimage signal data in an interleaved manner to generate dissolved andairspace images. In some embodiments, two batches or breath-holddeliveries of ¹²⁹Xe can be used. That is, one batch of gas may make theairspace image, and one batch of gas may make the dissolved image.However, in some embodiments, a scanning sequence can be used thatswitches the scanner frequency from gas to dissolved phase and backagain and acquires portions of the gas and dissolved image data sets inan interleaved manner.

Referring now to FIGS. 9A and 9B, a data processing system 316 is shownthat may be used to provide the ¹²⁹Xe dissolved phase MRI signaldecomposition (FIG. 9A) or the NMR spectra evaluation module (FIG. 9B).Thus, in accordance with some embodiments of the present invention, thesystem 316 comprises a memory 336 that communicate with a processor 300.The data processing system 316 may further include an input/output (I/O)circuits and/or data port(s) 346 that also communicate with theprocessor 300. The system 316 may include removable and/or fixed media,such as floppy disks, ZIP drives, hard disks, or the like, as well asvirtual storage, such as a RAMDISK. The I/O data port(s) 346 may be usedto transfer information between the data processing system 316 andanother computer system or a network (e.g., the Internet). Thesecomponents may be conventional components, such as those used in manyconventional computing devices, and their functionality, with respect toconventional operations, is generally known to those skilled in the art.

FIGS. 9A and 9B illustrate the processor 300 and memory 336 that may beused in embodiments of systems in accordance with some embodiments ofthe present invention. The processor 300 communicates with the memory336 via an address/data bus 348. The processor 300 may be, for example,a commercially available or custom microprocessor. The memory 336 isrepresentative of the one or more memory devices containing the softwareand data used for providing ¹²⁹Xe MRI image data or ¹²⁹XE NMR spectradata in accordance with some embodiments of the present invention. Thememory 336 may include, but is not limited to, the following types ofdevices: cache, ROM, PROM, EPROM, EEPROM, flash, SRAM, and DRAM.

As shown in FIGS. 9A and 9B, the memory 336 may contain up to two ormore categories of software and/or data: an operating system 352, I/ODevice Drivers 358, data 356 and application programs 354. FIG. 9Aillustrates that the data 356 can include patient image data 326 andFIG. 9B illustrates that data 356 can include patient NMR spectra data326′.

As will be appreciated by those of skill in the art, the operatingsystem 352 may be any operating system suitable for use with a dataprocessing system, such as IBM®, OS/2®, AIX® or zOS® operating systemsor Microsoft® Windows®95, Windows98, Windows2000 or WindowsXP operatingsystems Unix or Linux™. IBM, OS/2, AIX and zOS are trademarks ofInternational Business Machines Corporation in the United States, othercountries, or both while Linux is a trademark of Linus Torvalds in theUnited States, other countries, or both. Microsoft and Windows aretrademarks of Microsoft Corporation in the United States, othercountries, or both. The input/output device drivers 358 typicallyinclude software routines accessed through the operating system 352 bythe application programs 354 to communicate with devices such as theinput/output circuits 346 and certain memory 336 components. Theapplication programs 354 are illustrative of the programs that implementthe various features of the circuits and modules according to someembodiments of the present invention. Finally, the data 356 representsthe static and dynamic data used by the application programs 354 theoperating system 352 the input/output device drivers 358 and othersoftware programs that may reside in the memory 336.

As further illustrated in FIG. 9A, according to some embodiments of thepresent invention, application programs 354 may optionally include aDixon Signal Decomposition and/or Signal Differentiation Module 325 thatcan be used to generate one or more of an RBC Image and/or a BarrierImage or differentiate the signal into the appropriate respective imagedata sets. FIG. 9B illustrates the application programs 354 which mayoptionally include a dynamic ¹²⁹Xe dissolved phase spectroscopy module327 that can obtain RBC spectra and barrier spectra and a peakcomparison module 328. The application program 354 may be located in alocal server (or processor) and/or database or a remote server (orprocessor) and/or database in the MRI scanner, or combinations of localand remote databases and/or servers.

While the present invention is illustrated with reference to theapplication programs 354 with Modules 325 (in FIG. 9A) and 327 and 328(in FIG. 9B), as will be appreciated by those of skill in the art, otherconfigurations fall within the scope of the present invention. Forexample, rather than being application programs 354 these circuits andmodules may also be incorporated into the operating system 352 or othersuch logical division of the data processing system. Furthermore, whilethe application program 354 is illustrated in a single data processingsystem, as will be appreciated by those of skill in the art, suchfunctionality may be distributed across one or more data processingsystems in, for example, the type of client/server arrangement describedabove. Thus, the present invention should not be construed as limited tothe configurations illustrated in FIG. 6 but may be provided by otherarrangements and/or divisions of functions between data processingsystems. For example, although FIGS. 9A and 9B are illustrated as havingvarious circuits and modules, one or more of these circuits or modulesmay be combined or separated without departing from the scope of thepresent invention.

Although FIGS. 9A and 9B illustrate exemplary hardware/softwarearchitectures that may be used, it will be understood that the presentinvention is not limited to such a configuration but is intended toencompass any configuration capable of carrying out operations describedherein. Moreover, the functionality of the data processing systems andthe hardware/software architectures may be implemented as a singleprocessor system, a multi-processor system, or even a network ofstand-alone computer systems, in accordance with various embodiments ofthe present invention.

Computer program code for carrying out operations of data processingsystems discussed above with respect to the figures may be written in ahigh-level programming language, such as Java, C, and/or C++, fordevelopment convenience. In addition, computer program code for carryingout operations of embodiments of the present invention may also bewritten in other programming languages, such as, but not limited to,interpreted languages. Some modules or routines may be written inassembly language or even micro-code to enhance performance and/ormemory usage. It will be further appreciated that the functionality ofany or all of the program modules may also be implemented using discretehardware components, one or more application specific integratedcircuits (ASICs), or a programmed digital signal processor ormicrocontroller.

The present invention is described herein with reference to flowchartand/or block diagram illustrations of methods, systems, and computerprogram products in accordance with exemplary embodiments of theinvention. These flowchart and/or block diagrams further illustrateexemplary operations for administering and/or providing calendar-basedtime limited passcodes, in accordance with some embodiments of thepresent invention. It will be understood that each block of theflowchart and/or block diagram illustrations, and combinations of blocksin the flowchart and/or block diagram illustrations, may be implementedby computer program instructions and/or hardware operations. Thesecomputer program instructions may be provided to a processor of ageneral purpose computer, a special purpose computer, or otherprogrammable data processing apparatus to produce a machine, such thatthe instructions, which execute via the processor of the computer orother programmable data processing apparatus, create means and/orcircuits for implementing the functions specified in the flowchartand/or block diagram block or blocks.

These computer program instructions may also be stored in a computerusable or computer-readable memory that may direct a computer or otherprogrammable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer usable orcomputer-readable memory produce an article of manufacture includinginstructions that implement the function specified in the flowchartand/or block diagram block or blocks.

The computer program instructions may also be loaded onto a computer orother programmable data processing apparatus to cause a series ofoperational steps to be performed on the computer or other programmableapparatus to produce a computer implemented process such that theinstructions that execute on the computer or other programmableapparatus provide steps for implementing the functions specified in theflowchart and/or block diagram block or blocks.

The flowcharts and block diagrams illustrate the architecture,functionality, and operations of some embodiments of methods, systems,and computer program products. In this regard, each block represents amodule, segment, or portion of code, which comprises one or moreexecutable instructions for implementing the specified logicalfunction(s). It should also be noted that in other implementations, thefunction(s) noted in the blocks might occur out of the order noted. Forexample, two blocks shown in succession may, in fact, be executedsubstantially concurrently or the blocks may sometimes be executed inthe reverse order, depending on the functionality involved.

In summary, embodiments of the invention can be used to create images of¹²⁹Xe dissolved in lung tissue barrier and red blood cells within thegas exchange regions of the lung. Embodiments of the invention canemploy radial encoding, continuous ¹²⁹Xe replenishment from the airspaces, and signal averaging, to overcome the short T₂* and lowinstantaneous ¹²⁹Xe magnetization in the barrier and RBC phases. Theseimages exhibit SNR and resolution that is consistent with expectationsbased on gas phase magnetization, xenon solubility, and tissue density.By separating the ¹²⁹Xe image into barrier and RBC components, imagingof the alveolar-capillary gas transfer process a fundamental role of thelung, can be achieved. The images showing an absence of ¹²⁹Xereplenishment in red blood cells in regions of injury are consistentwith theoretical expectations based on decreased diffusion transfer of¹²⁹Xe from alveoli to red blood cells. Methods of quantifying gastransfer efficiency is also proposed by using the ratio of RBC/barrierpixel counts.

Some embodiments of the present invention have been illustrated hereinby way of example. Many variations and modifications can be made to theembodiments without substantially departing from the principles of thepresent invention. All such variations and modifications are intended tobe included herein within the scope of the present invention, as setforth in the following claims.

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That which is claimed:
 1. A method for providing MRI data of pulmonarygas exchange and/or alveolar-capillary barrier status, comprising:transmitting an RF MRI excitation pulse sequence configured to excitedissolved phase hyperpolarized ¹²⁹Xe in a gas exchange region of a lungof a subject; obtaining MRI image data of dissolved phase hyperpolarized¹²⁹Xe in a red blood cell (RBC) compartment in the gas exchange regionof the lung of the subject based on the transmission of the RF MRIexcitation pulse sequence; and generating at least one 3-D dissolvedphase hyperpolarized ¹²⁹Xe MRI image of the gas exchange region of thelung using the obtained dissolved phase hyperpolarized ¹²⁹Xe MRI imagedata of the RBC compartment.
 2. A method according to claim 1, whereinthe obtaining step is carried out using a RF pulse repetition time ofbetween about 0-60 ms.
 3. A method according to claim 1, furthercomprising visually indicating differences in barrier thickness in theat least one generated 3-D image of the lung over a lung volume usingcolor and/or opacity differences for facilitating assessment of at leastone of pulmonary gas exchange, barrier thickness, or barrier function.4. A method according to claim 1, further comprising: obtainingdissolved phase ¹²⁹Xe MRI barrier compartment image signal data of thegas exchange region of the lung based on the transmitting step;generating at least one 3-D dissolved phase ¹²⁹Xe MRI barriercompartment image of the lung based on the obtained barrier compartmentimage signal data; and displaying the generated barrier compartment 3-Dlung image substantially concurrently with the generated RBC compartment3-D lung image.
 5. A method according to claim 4, wherein image signaldata for the at least one ¹²⁹Xe MM barrier image and the image signaldata of the ¹²⁹Xe MRI RBC compartment are received substantiallyconcurrently on different receiver channels associated with an MRIscanner.
 6. A method according to claim 2, wherein the obtained ¹²⁹XeMRI RBC image signal data is obtained using about a 90 degree RFexcitation pulse.
 7. A method according to claim 4, wherein the step ofobtaining the dissolved phase ¹²⁹Xe MRI RBC image signal data and thestep of obtaining the dissolved phase ¹²⁹Xe MM barrier image signal dataeach comprise obtaining a plurality of respective signal image data atdifferent RF pulse repetition times (TR) of between about 0-60 ms todirectly define signal replenishment on a pixel by pixel basis, andwherein the method further comprises: determining (i) whether there is anon uniform barrier thickness based on the obtained images.
 8. A methodaccording to claim 1, wherein the transmitting step is carried out usinga radial imaging sequence with sub-millisecond echo times to generatethe obtained image signal data.
 9. A method according to claim 1,wherein the transmitting step is carried out using a spin-echo imagingsequence to generate the obtained image signal data.
 10. A methodaccording to claim 1, further comprising concurrently obtaining MRIimage data of dissolved phase hyperpolarized ¹²⁹Xe in barriercompartment in the gas exchange region of the lung of the subject basedon the transmission of the RF MRI excitation pulse sequence, wherein theobtained ¹²⁹Xe MRI RBC and barrier image signal data is defined based ona one-point Dixon mathematical evaluation of MRI dissolved phase ¹²⁹Xesignal data comprising the RBC signal data and barrier image signaldata, wherein the transmitting step is carried out with a pulse sequencehaving sub-millisecond echo times, and wherein there is about a 90degree phase difference between the RBC compartment and the barriercompartment signals.
 11. A method according to claim 1, furthercomprising: obtaining dissolved phase hyprepolarized ¹²⁹Xe MRI barriercompartment image signal data of the gas exchange region of the lungbased on the transmitting step; obtaining gas-phase hyperpolarized ¹²⁹XeMRI image signal data of the lung of the patient; electronicallygenerating a field map of spatially varying field shifts correspondingto magnetic field inhomogeneity associated with an MRI scanner used togenerate the obtained gas-phase ¹²⁹Xe image signal data; andelectronically correcting signal data associated with dissolved phase¹²⁹Xe MRI RBC and barrier image signal data using the generatedfield-map to generate the at least one 3-D image of the gas exchangeregion of the lung.
 12. A method according to claim 4, the methodfurther comprising comparing the ¹²⁹Xe RBC and barrier images todirectly detect dissolved phase ¹²⁹Xe MRI signal attenuation in the¹²⁹Xe RBC image, wherein signal attenuation is associated with barrierthickness.
 13. A method according to claim 4, the method furthercomprising generating a ratio image using ratios of pixel values of the¹²⁹Xe RBC and barrier image data to detect dissolved phase ¹²⁹Xe MRIsignal attenuation associated with barrier thickness.
 14. A methodaccording to claim 1, further comprising evaluating whether a drugadministered to the patient is associated with alveolar inflammationbased on the ¹²⁹Xe MRI RBC image.
 15. A method according to claim 1,further comprising evaluating efficacy of a drug administered to thepatient to improve pulmonary gas exchange based on the ¹²⁹Xe MRI RBCimage.
 16. A method according to claim 1, wherein the step of obtainingthe MRI RBC image data is carried out in a single breath hold delivery,the method further comprising: obtaining MRI image data of dissolvedphase hyperpolarized ¹²⁹Xe of a blood-gas barrier separating airspacefrom capillary blood based on the same single-breath hold delivery ofhyperpolarized ¹²⁹Xe gas; and wherein the generating the at least one3-D MRI image of the gas exchange region of the lung is carried outusing the obtained ¹²⁹Xe dissolved phase MRI image data of the blood-gasbarrier and the RBC compartment.
 17. A method according to claim 1,wherein the obtaining step is carried out using a single breath-holddelivery of hyperpolarized ¹²⁹Xe gas, and wherein the patient is ahuman.
 18. A method according to claim 1, wherein the obtaining step iscarried out by interleaving acquisition of the dissolved phase MRIsignal of the RBC compartment with acquisition of gas phase image signaldata during a single breath hold delivery of ¹²⁹Xe hyperpolarized gas.19. A method of providing pulmonary gas exchange information of apatient, comprising: electronically displaying a first 3-D MRI image ofa gas exchange region of the lung of a human patient on a display, theimage generated using hyperpolarized ¹²⁹Xe dissolved phase image data ofan RBC compartment of the patient using a single-breath hold deliveryamount of ¹²⁹Xe hyperpolarized gas; electronically displaying adifferent 3-D MRI image of the lung of the patient on the display usinghyperpolarized ¹²⁹Xe dissolved phase image data of a barrier compartmentfrom the same breath hold delivery of the ¹²⁹Xe hyperpolarized gas; andelectronically displaying a third 3-D MRI image of the lung of thepatient on the display using ¹²⁹Xe gas phase image data from the same ora different ¹²⁹Xe hyperpolarized gas breath-hold delivery.
 20. Themethod of claim 19, wherein the three different images are concurrentlydisplayed on the display.
 21. The method of claim 19, wherein the 3-Dimage of the barrier compartment visually shows differences in barrierthickness using color or opacity differences over an image volume basedon signal attenuation of pixels in the RBC compartment that representsregions of diffusion barrier thickening.
 22. A method of providingpulmonary gas exchange information using MRI lung images of a humanpatient, comprising: providing an electronic 3-D MRI image of a lung ofa patient using dissolved phase hyperpolarized ¹²⁹Xe image signal of abarrier compartment from a single-breath hold delivery of ¹²⁹Xehyperpolarized gas; and providing an electronic 3-D MRI image of thelung of the patient using dissolved phase hyperpolarized ¹²⁹Xe imagesignal of a RBC compartment from the same single-breath hold delivery of¹²⁹Xe hyperpolarized gas.
 23. The method of claim 22, furthercomprising: providing a 3-D MRI image of the lung of the patient usinggas phase hyperpolarized ¹²⁹Xe image signal, wherein image signal forthe 3-D images are acquired using an interleaved acquisition ofdissolved phase and gas phase image signal data during the single breathhold.
 24. The method of claim 22, further comprising electronicallyevaluating the dissolved phased ¹²⁹Xe hyperpolarized ¹²⁹Xe image signalto generate the 3-D images using a 1-point Dixon technique of the RBCcompartment and the barrier compartment signals obtained at about a 90degree phase difference, wherein the dissolved phase 129Xe image signalis obtained using a pulse sequence having sub-millisecond echo times.25. A method according to claim 1, wherein the obtaining is carried outusing one breath-hold delivery of hyperpolarized 129Xe gas, the methodfurther comprising: obtaining dissolved phase hyperpolarized ¹²⁹Xe MRIbarrier compartment image signal data of the gas exchange region of thelung substantially concurrently with the dissolved phase hyperpolarized129Xe RBC image signal data based on the transmitting step;differentiating MRI dissolved phase ¹²⁹Xe signal data comprising bothRBC signal data and barrier signal data using a one-point Dixontechnique, wherein there is about a 90 degree phase difference betweenthe RBC compartment and the barrier compartment signals; electronicallycorrecting magnetic field (B₀) inhomogeneity associated with theone-point Dixon differentiation of the dissolved phase ¹²⁹Xe MRI RBC andbarrier image signal data using airspace image data of hyperpolarized129Xe gas to generate the at least one 3-D image of the gas exchangeregion of the lung.
 26. A method according to claim 25, wherein thegenerating the at least one 3-D image of the lungs is carried out toshow variations in thickness in the blood gas barrier over a volume ofthe lung based on signal attenuation of the dissolved phase MRI RBCcompartment image.